Compositions and Formulations for Increasing Renal Function and Treatment and Prevention of Renal Diseases, and Methods of Production and Use Thereof

ABSTRACT

Nutritive polypeptides are provided herein. Also provided are various other embodiments including nucleic acids encoding the polypeptides, recombinant microorganisms that make the polypeptides, vectors for expressing the polypeptides, methods of making the polypeptides using recombinant microorganisms, compositions and formulations that comprise the polypeptides, and methods of using the polypeptides, compositions and formulations.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/882,211, filed Sep. 25, 2013, 61/882,214, filed Sep. 25, 2013,61/882,219, filed Sep. 25, 2013, 61/882,220, filed Sep. 25, 2013,61/882,225, filed Sep. 25, 2013, 61/882,229, filed Sep. 25, 2013,61/882,232, filed Sep. 25, 2013, 61/882,234, filed Sep. 25, 2013,61/882,235, filed Sep. 25, 2013, 61/882,240, filed Sep. 25, 2013,61/882,129, filed Sep. 25, 2013, 61/882,243, filed Sep. 25, 2013,61/882,246, filed Sep. 25, 2013, 61/882,250, filed Sep. 25, 2013,61/882,254, filed Sep. 25, 2013, 61/882,260, filed Sep. 25, 2013,61/882,264, filed Sep. 25, 2013, 61/882,267, filed Sep. 25, 2013,61/882,271, filed Sep. 25, 2013, 61/882,274, filed Sep. 25, 2013,61/882,180, filed Sep. 25, 2013, 61/882,189, filed Sep. 25, 2013,61/882,198, filed Sep. 25, 2013, 61/882,212, filed Sep. 25, 2013,61/882,222, filed Sep. 25, 2013, 61/882,300, filed Sep. 25, 2013,61/882,295, filed Sep. 25, 2013, and 61/882,305, filed Sep. 25, 2013;the entire disclosures of which are hereby incorporated by reference intheir entirety for all purposes.

BACKGROUND

Dietary protein is an essential nutrient for human health and growth.The World Health Organization recommends that dietary protein shouldcontribute approximately 10 to 15% of energy intake when in energybalance and weight stable. Average daily protein intakes in variouscountries indicate that these recommendations are consistent with theamount of protein being consumed worldwide. Meals with an average of 20to 30% of energy from protein are representative of high-protein dietswhen consumed in energy balance. The body cannot synthesize certainamino acids that are necessary for health and growth, and instead mustobtain them from food. These amino acids, called “essential aminoacids”, are Histidine (H), Isoleucine (I), Leucine (L), Lysine (K),Methionine (M), Phenylalanine (F), Threonine (T), Tryptophan (W), andValine (V). Dietary protein sources that provide all the essential aminoacids are referred to as “high quality” proteins. Animal foods such asmeat, fish, poultry, eggs, and dairy products are generally regarded ashigh quality protein sources that provide a good balance of essentialamino acids. Casein (a protein commonly found in mammalian milk, makingup 80% of the proteins in cow milk) and whey (the protein in the liquidthat remains after milk has been curdled and strained) are major sourcesof high quality dietary protein. Foods that do not provide a goodbalance of essential amino acids are referred to as “low quality”protein sources. Most fruits and vegetables are poor sources of protein.Some plant foods including beans, peas, lentils, nuts and grains (suchas wheat) are better sources of protein but may have allergenicityissues. Soy, a vegetable protein manufactured from soybeans, isconsidered by some to be a high quality protein. Studies of high proteindiets for weight loss have shown that protein positively affects energyexpenditure and lean body mass. Further studies have shown thatovereating produces significantly less weight gain in diets containingat least 5% of energy from protein, and that a high-protein dietdecreases energy intake. Proteins commonly found in foods do notnecessarily provide an amino acid composition that meets the amino acidrequirements of a mammal, such as a human, in an efficient manner. Theresult is that, in order to attain the minimal requirements of eachessential amino acid, a larger amount of total protein must be consumedin the diet than would be required if the quality of the dietary proteinwere higher. By increasing the quality of the protein in the diet it ispossible to reduce the total amount of protein that must be consumedcompared to diets that include lower quality proteins. Traditionally,desirable mixtures of amino acids, such as mixtures comprising essentialamino acids, have been provided by hydrolyzing a protein with relativelyhigh levels of essential amino acids, such as whey protein, and/or bycombining free amino acids in a mixture that optionally also includes ahydrolyzed protein such as whey. Mixtures of this type may have a bittertaste, undesirable mouthfeel and are poorly soluble, and may be deemedunsuitable or undesirable for certain uses. As a result, such mixturessometimes include flavoring agents to mask the taste of the free aminoacids and/or hydrolyzed protein. In some cases compositions in which aproportion of the amino acid content is provided by polypeptides orproteins are found to have a better taste than compositions with a highproportion of total amino acids provided as free amino acids and/orcertain hydrolyzed proteins. The availability of such compositions hasbeen limited, however, because nutritional formulations havetraditionally been made from protein isolated from natural foodproducts, such as whey isolated from milk, or soy protein isolated fromsoy. The amino acid profiles of those proteins do not necessarily meetthe amino acid requirements for a mammal. In addition, commodityproteins typically consist of mixtures of proteins and/or proteinhydrolysates which can vary in their protein composition, thus leadingto unpredictability regarding their nutritional value. Moreover, thelimited number of sources of such high quality proteins has meant thatonly certain combinations of amino acids are available on a large scalefor ingestion in protein form. The agricultural methods required for thesupply of high quality animal protein sources such as casein and whey,eggs, and meat, as well as plant proteins such as soy, also requiresignificant energy inputs and have potentially deleterious environmentalimpacts.

Accordingly, it would be useful in certain situations to havealternative sources and methods of supplying proteins for mammalianconsumption. One feature that can enhance the utility of a nutritiveprotein is its solubility. Nutritive proteins with higher solubility canexhibit desirable characteristics such as increased stability,resistance to aggregation, and desirable taste profiles. For example, anutritive protein that exhibits enhanced solubility can be formulatedinto a beverage or liquid formulation that includes a high concentrationof nutritive protein in a relatively low volume of solution, thusdelivering a large dose of protein nutrition per unit volume. A solublenutritive protein can be useful in sports drinks or recovery drinkswherein a user (e.g., an athlete) wants to ingest nutritive proteinbefore, during or after physical activity. A nutritive protein thatexhibits enhanced solubility can also be particularly useful in aclinical setting wherein a subject (e.g., a patient or an elderlyperson) is in need of protein nutrition but is unable to consume solidfoods or large volumes of liquids.

SUMMARY OF THE INVENTION

In one aspect, the invention provides methods of preventing or reducingloss of muscle mass and/or muscle function in a human subject, includingthe steps of: i) identifying a human subject suffering from or at riskof a renal disease, and ii) administering to the human subject anutritional formulation in an amount sufficient to prevent or reduce aloss of muscle mass and/or muscle function, wherein the nutritionalformulation includes an isolated nutritive polypeptide including anamino acid sequence at least about 90% identical over at least about 50amino acids to a polypeptide sequence provided herein; wherein theformulation includes at least 1.0 g of the nutritive polypeptide;wherein the formulation is present as a liquid, semi-liquid or gel in avolume not greater than about 500 ml or as a solid or semi-solid in atotal mass not greater than about 200 g; and wherein the formulation issubstantially free of non-comestible products. In one embodiment, thehuman subject is suffering from a renal disease and has received one ormore doses of a pharmaceutical composition, wherein administration ofthe pharmaceutical composition increases a risk of loss of muscle massand/or muscle function. In one embodiment, the human subject issuffering from a renal disease and has received one or more doses of apharmaceutical composition, wherein i) the disease, disorder orcondition or ii) the administration of the pharmaceutical composition,or both i) and ii) increases a risk of loss of muscle mass and/or musclefunction.

In another aspect, the invention provides methods of treating a musclewasting disease, disorder or condition in a human subject suffering froma renal disease, including the step of administering to the humansubject a nutritional formulation in an amount sufficient to treat suchmuscle wasting disease, disorder or condition, wherein the nutritionalformulation includes an isolated nutritive polypeptide including anamino acid sequence at least about 90% identical over at least about 50amino acids to a polypeptide sequence provided herein: wherein theformulation includes at least 1.0 g of the nutritive polypeptide. In oneembodiment, the formulation is administered on a dosage schedulesufficient to provide substantial protein nutrition to the human subjectin the absence of consumption by the subject of anagriculturally-derived food product.

In another aspect, the invention provides methods of reducing the riskof a human subject developing a disease, disorder or conditioncharacterized or exacerbated by protein malnourishment, including thesteps of (i) identifying the human subject as suffering from a renaldisease and being at risk of developing the protein malnourishmentdisease, disorder or condition; and (ii) administering in one or moredoses a nutritional formulation including an isolated nutritivepolypeptide including an amino acid sequence at least about 90%identical over at least about 50 amino acids to a polypeptide sequenceprovided herein; wherein the formulation includes at least 1.0 g of thenutritive polypeptide. In one embodiment, the human subject is at riskof developing malnutrition or protein malnutrition. In one embodiment,the human subject exhibits sarcopenia and/or cachexia. In oneembodiment, the human subject has an inflammatory reaction or anautoimmune disorder. In one embodiment, the human subject has end-stagerenal disease. In one embodiment, the human subject has chronic renalfailure, acute renal failure, glomerulonephritis, glomerulonephrosis,tubular nephritis, interstitial nephritis, or nephrotic syndrome. In oneembodiment, the human subject has undergone a surgical procedure. In oneembodiment, the human subject has a urea cycle disorder. In oneembodiment, the nutritional formulation is administered in conjunctionwith a surgical therapy. In one embodiment, the nutritional formulationis administered in conjunction with an exercise regimen. In oneembodiment, the nutritional formulation is administered as an adjunct toadministration a pharmaceutical composition. In one embodiment, thehuman subject has renal failure.

In another aspect, the invention provides methods of increasing muscleanabolism in a human subject suffering from a renal disease, includingadministering to a human subject in one or more doses a nutritionalformulation including an isolated nutritive polypeptide including anamino acid sequence at least about 90% identical over at least about 50amino acids to a polypeptide sequence provided herein; wherein theformulation includes at least 1.0 g of the nutritive polypeptide,wherein the nutritive formulation is administered to the human subjectat a frequency sufficient to increase muscle anabolism in the subjectafter the administration thereof.

In another aspect, the invention provides methods of formulating anutritional product for use in treating a human subject, including thesteps of providing to a human subject suffering from a renal disease, anutritive composition including an isolated nutritive polypeptideincluding an amino acid sequence at least about 90% identical over atleast about 50 amino acids to a polypeptide sequence provided herein:and formulating the nutritive polypeptide with an acceptable excipient,wherein the isolated nutritive polypeptide has an aqueous solubility atpH 7 of at least 12.5 g/L, and wherein the isolated nutritivepolypeptide has a simulated gastric digestion half-life of less than 30minutes. In one embodiment, the methods further include combining thenutritive composition with at least one of a tastant, a nutritionalcarbohydrate and a nutritional lipid, wherein the product is present asa liquid, semi-liquid or gel in a volume not greater than about 500 mlor as a solid or semi-solid in a total mass not greater than about 200g. In one embodiment, the product is substantially free of i)non-comestible products; and/or ii) a salt selected from sodium,potassium and chloride; and/or iii) an electrolyte selected fromhydrogen phosphate, dihydrogen phosphate, and hydrogen bicarbonate.

In another aspect, the invention provides methods for selecting an aminoacid sequence of a nutritive polypeptide wherein the nutritivepolypeptide is suitable for use in treating a human subject sufferingfrom a renal disease, including i) providing a library of amino acidsequences including a plurality of amino acid sequences, ii) identifyingin the library one or more amino acid sequences including at least oneamino acid of interest, and iii) selecting the one or more identifiedamino acid sequences, thereby selecting an amino acid sequence of anutritive polypeptide.

In another aspect, the invention provides methods for selecting an aminoacid sequence of a nutritive polypeptide wherein the nutritivepolypeptide is suitable for use in treating a human subject sufferingfrom a renal disease, including i) providing a library of amino acidsequences including a plurality of amino acid sequences, ii) identifyingin the library one or more amino acid sequences including a ratio of atleast one amino acid residues of interest to total amino acid residuesgreater than or equal to a selected ratio, and iii) selecting the one ormore identified amino acid sequences, thereby selecting an amino acidsequence of a nutritive polypeptide.

In another aspect, the invention provides methods for selecting an aminoacid sequence of a nutritive polypeptide wherein the nutritivepolypeptide is suitable for use in treating a human subject sufferingfrom a renal disease, including i) providing a library of amino acidsequences including a plurality of amino acid sequences, ii) identifyingin the library one or more amino acid sequences including a ratio of atleast one amino acid residues of interest to total amino acid residuesless than or equal to a selected ratio, and iii) selecting the one ormore identified amino acid sequences, thereby selecting an amino acidsequence of a nutritive polypeptide.

In another aspect, the invention provides nutritive formulations for thetreatment or prevention of a muscle wasting disease, disorder orcondition in a human subject suffering from a renal disease, includingan isolated nutritive polypeptide including an amino acid sequence atleast about 90% identical over at least about 50 amino acids to apolypeptide sequence provided herein: wherein the nutritive polypeptideis present in an amount sufficient to provide a nutritional benefit to ahuman subject having or at risk of having reduced protein absorptioncapacity. In one embodiment, the polypeptide sequence includes a ratioof essential amino acid residues to total amino acid residues of atleast 34% and wherein the polypeptide sequence is nutritionallycomplete. In one embodiment, the essential amino acids present in thenutritive polypeptide are substantially bioavailable. In one embodiment,the isolated nutritive polypeptide has an aqueous solubility at pH 7 ofat least 12.5 g/L. In one embodiment, the isolated nutritive polypeptidehas a simulated gastric digestion half-life of less than 30 minutes. Inone embodiment, the nutritive polypeptide is formulated in apharmaceutically acceptable carrier. In one embodiment, the nutritivepolypeptide is formulated in or as a food or a food ingredient. In oneembodiment, the nutritive polypeptide is formulated in or as a beverageor a beverage ingredient. In one embodiment, the amino acid sequenceencodes an enzyme having a primary activity, and wherein the nutritivepolypeptide substantially lacks the primary activity. In one embodiment,the formulation is present as a liquid, semi-liquid or gel in a volumenot greater than about 500 ml or as a solid or semi-solid in a totalmass not greater than about 200 g. In one embodiment, the nutritivepolypeptide includes an amino acid sequence at least about 90% identicalto an edible species polypeptide or fragment thereof at least 50 aminoacids in length, wherein the amino acid sequence has less than about 50%identity over at least 25 amino acids to a known allergen. In oneembodiment, the formulations further include a component selected from atastant, a protein mixture, a polypeptide, a peptide, a free amino acid,a carbohydrate, a lipid, a mineral or mineral source, a vitamin, asupplement, an organism, a pharmaceutical, and an excipient. In oneembodiment, the human subject is suffering from an acute kidney injuryor a chronic kidney disease. In one embodiment, the amino acid sequencecontains a density of essential amino acids about equal to or greaterthan the density of essential chain amino acids present in a full-lengthreference nutritional polypeptide or a reference polypeptide-containingmixture. In one embodiment, the amino acid sequence contains: i) adensity of at least one selected branched chain amino acid about equalto or greater than the density of the selected branched chain amino acidpresent in a full-length reference nutritional polypeptide or areference polypeptide-containing mixture; ii) a density of arginineabout equal to or greater than the density of arginine present in thefull-length reference nutritional polypeptide or the referencepolypeptide-containing mixture; and/or iii) a density of glutamineand/or glutamic acid lower than the density of glutamine and/or glutamicacid present in the full-length reference nutritional polypeptide or thereference polypeptide-containing mixture.

In another aspect, the invention provides formulations including atleast one nutritive polypeptide including an amino acid sequence atleast about 99% identical to an edible species polypeptide capable ofbeing secreted from a microorganism, wherein the nutritive polypeptideis present in the formulation in an amount sufficient to provide anutritional benefit equivalent to or greater than at least about 2% of areference daily intake value of protein.

In another aspect, the invention provides nutritive formulations for thetreatment or prevention of a muscle wasting disease, disorder orcondition in a human subject suffering from a renal disease, including anutritive amino acid composition including a plurality of free aminoacids including an amino acid ratio at least about 90% identical to anamino acid ratio of a polypeptide sequence provided herein, wherein thenutritive amino acid composition is nutritionally complete; wherein thenutritive amino acid composition is present in an amount sufficient toprovide a nutritional benefit to a human subject having reduced proteinabsorption capacity. In one embodiment, the formulation is present as aliquid, semi-liquid or gel in a volume not greater than about 500 ml oras a solid or semi-solid in a total mass not greater than about 200 g.

In another aspect, the invention provides methods of treating orreducing the severity of a renal disease in a human subject, includingthe steps of: i) identifying a human subject suffering from or at riskof developing a renal disease, and ii) administering to the humansubject a nutritional formulation in an amount sufficient to treat orprevent the renal disease, wherein the nutritional formulation includesan isolated nutritive polypeptide including an amino acid sequence atleast about 90% identical over at least about 50 amino acids to apolypeptide sequence provided herein; wherein the formulation includesat least 1.0 g of the nutritive polypeptide; wherein the formulation ispresent as a liquid, semi-liquid or gel in a volume not greater thanabout 500 ml or as a solid or semi-solid in a total mass not greaterthan about 200 g; and wherein the formulation is substantially free ofnon-comestible products. In one embodiment, the human subject has anephrotic syndrome and suffers from a muscle wasting condition.

BRIEF DESCRIPTION OF THE FIGURES

These and other features, aspects, and advantages of the presentinvention will become better understood with regard to the followingdescription, and accompanying drawings, where:

FIG. 1 is an image demonstrating SDS-PAGE analysis of the purificationof SEQID-00105 by IMAC.

FIG. 2 is a chart demonstrating net charge per amino acid as a functionof pH for nutritive polypeptides predicted to bind to either anion orcation exchange resin. (1) SEQID-00105, (2) SEQID-00008, (3)SEQID-00009, (4) SEQID-00475, (5) SEQID-00472, (6) SEQID-00640, (7)SEQID-00019.

FIG. 3 is a chart demonstrating total charge per amino acid over a rangeof pHs for exemplary nutritive polypeptides. (1) SEQID-00475, (2)SEQID-00009, (3) SEQID-00478, (4) SEQID-00433, (5) SEQID-00472.

FIG. 4 is a chart demonstrating purity of SEQID-00009 is as a functionof ammonium sulfate concentration.

FIG. 5 is an image demonstrating SDS-PAGE analysis demonstratingsecretion of SEQID-00409 (left) and SEQID-00420 (right) with new signalpeptide compared to native signal peptide.

FIG. 6 is a chart demonstrating supernatant concentration of GLP-1(7-36) detected in the supernatant following stimulation, error bars arethe standard deviation of the technical replicates.

FIG. 7 is a chart demonstrating average blood glucose values over timeduring OGTT of vehicle, SEQID-00105, Arginine, and SEQID-00338. Theerror bars shown are the standard errors of the mean.

FIG. 8 is a chart demonstrating the area under curve for blood glucoseintegrated from 0-120 minutes (Left) and from 0-60 minutes (Right) afteracute dosing of SEQID-00105, Arginine, and SEQID-00338.

FIG. 9 is a chart demonstrating average plasma insulin concentration forn=6 rats per treatment group over time. The error bars show the standarderror of the mean.

FIG. 10 is a chart demonstrating plasma insulin area under curveintegrated between 0-240 and 0-60 minutes for all treatment groups. Theerror bars show the standard error of the mean.

FIG. 11 is a chart demonstrating average plasma GLP-1 concentration forn=6 rats per treatment group over time. The error bars shown herecorrespond to the standard error of the mean.

FIG. 12 is a chart demonstrating average blood glucose values over time.The error bars shown are the standard errors of the mean.

FIG. 13 is a chart demonstrating integrated AUC for each treatment groupbetween the time of glucose challenge (0 min.) and 60 minutes, andbetween time 0 and 120 minutes. The error bars shown are the standarderrors of the mean.

FIG. 14 is a chart demonstrating average plasma insulin concentrationfor n=6 rats per treatment group in vehicle & SEQID-00105 and n=5 ratsper treatment group in the case of SEQID-00338 over the course of theexperiment. The error bars shown are the standard errors of the mean.

FIG. 15 is a chart demonstrating integrated area under the curve forvehicle, SEQID-00105 and SEQID-00338 between 0 and 90 minutes andbetween 0 and 60 minutes. Error bars shown here correspond to thestandard error of the mean.

FIG. 16 is a chart demonstrating average plasma GLP-1 concentration forn=6 rats per treatment group for vehicle and SEQID-00105 and n=5 ratsfor SEQID-00338 over the course of the experiment. Error bars shown herecorrespond to the standard error of the mean.

FIG. 17 is a chart demonstrating area under curve for GLP-1 (7-36) foreach treatment group integrated to 0-90 and 0-60 minutes. Error barsshown here correspond to the standard error of the mean.

FIG. 18 is a chart demonstrating average blood glucose values duringKOGTT of vehicle, SEQID-00105, Alogliptin, and the combination for n=6rats per treatment group. Error bars shown here correspond to thestandard error of the mean.

FIG. 19 is a chart demonstrating AlphaLISA plasma insulin over time forvehicle and SEQID-00105 administered at three different doses. Errorbars shown here are the standard error of the mean.

FIG. 20 is a chart demonstrating AlphaLISA plasma insulin over time forvehicle and SEQID-00426, SEQID-00338, SEQID-00341. Error bars shown hereare the standard error of the mean.

FIG. 21 is a chart demonstrating integrated area under curves for plasmainsulin concentrations for SEQID-00105 at three doses between 0 and 240minutes and between 0 and 60 minutes. Error bars shown here are thestandard error of the mean.

FIG. 22 is a chart demonstrating integrated area under curves for plasmainsulin concentrations for vehicle, SEQID-00426, SEQID-00338, andSEQID-0034 I between 0 and 240 minutes and between 0 and 60 minutes.Error bars shown here are the standard error of the mean.

FIG. 23 is a chart demonstrating AlphaLISA plasma insulin over time forSEQID-00423, SEQID-00587, SEQID-00105. Error bars shown here are thestandard error of the mean.

FIG. 24 is a chart demonstrating AlphaLISA plasma insulin over time forvehicle SEQID-00424, SEQID-00425, and SEQID-00429. Error bars shown hereare the standard error of the mean.

FIG. 25 is a chart demonstrating integrated area under curves for plasmainsulin concentrations for vehicle, SEQID-00423, SEQID-00587, andSEQID-00105 between 0 and 240 minutes and between 0 and 60 minutes.Error bars shown here are the standard error of the mean.

FIG. 26 is a chart demonstrating integrated area under curves for plasmainsulin concentrations for vehicle, SEQID-00424, SEQID-00425, andSEQID-00429 between 0 and 240 minutes and between 0 and 60 minutes.Error bars shown here are the standard error of the mean.

FIG. 27 is a chart demonstrating ELISA plasma insulin over time forvehicle and SEQID-00105, SEQID-00240, and SEQID-00559. Error bars shownhere are the standard error of the mean.

FIG. 28 is a chart demonstrating integrated area under curves for plasmainsulin concentrations for vehicle, SEQID-00105, SEQID-00240, andSEQID-00559 between 0 and 240 minutes and 0 and 60 minutes. Error barsshown here are the standard error of the mean.

FIG. 29 is a chart demonstrating GLP-2 concentration over a 4 hour timecourse for vehicle and SEQID-00240, n=4 and n=5 rats, respectively.Error bars shown are the standard error of the mean.

FIG. 30 is a chart demonstrating integrated GLP-2 area under the curveover the first hour and the full 4 hours. Error bars shown are the 95%confidence interval.

FIG. 31 is a chart demonstrating average plasma insulin response toSEQID-00105 of all subjects over time.

FIG. 32 is a chart demonstrating average plasma insulin fold response toSEQID-00105 over baseline.

FIG. 33 is a chart demonstrating average plasma insulin response toSEQID-00426 of all subjects over time.

FIG. 34 is a chart demonstrating average plasma insulin fold response toSEQID-00426 over baseline.

FIG. 35 is a chart demonstrating average total Gastric InhibitoryPolypeptide (GIP) response of all patients to SEQID-00426.

FIG. 36 is a chart demonstrating a Gastric Inhibitory Polypeptide (GIP)fold response of all patients to SEQID-00426.

FIG. 37 is a chart demonstrating alphascreen signal (y-axis) measured atdifferent Leucine concentrations. Error bars shown are the standarddeviation of replicates.

FIG. 38 is a chart demonstrating Leucine Dose Response in Minimal AminoAcid Media in Primary RSKMC. Error bars shown are the standarddeviation.

FIG. 39 is a chart demonstrating In vitro Leucine Dose Response of rps6Phosphorylation in Isolate Soleus Muscle. Error bars shown are thestandard deviation.

FIG. 40 is a chart demonstrating In vitro Leucine Dose Response of ips6Phosphorylation in Isolated Gastrocnemius Muscle. Error bars shown arethe standard deviation.

FIG. 41 is a chart demonstrating In vitro Leucine Dose Response of rps6Phosphorylation in Isolate Extensor Digitorum Longus Muscle. Error barsshown are the standard deviation.

FIG. 42 is a chart demonstrating Combined Activity of Leu/Tyr/Arg onRPS6 Phosphorylation. Error bars shown are the standard deviation.

FIG. 43 is a chart demonstrating Arginine Stimulation of RPS6 in Leu/TyrBackground. Error bars shown are the standard deviation.

FIG. 44 is a chart demonstrating Leucine Stimulation of RPS6 in Arg/TyrBackground. Error bars shown are the standard deviation.

FIG. 45 is a chart demonstrating Tyrosine Stimulation of RPS6 in Arg/LeuBackground. Error bars shown are the standard deviation.

FIG. 46 is a chart demonstrating a time-course of free Leu releaseduring Pancreatin digest of SEQID-00105.

FIG. 47 is a chart demonstrating viscosity measured in centipoise forSEQID-0010S at 4 C (closed circles) and 25 C (open circles) and whey at4 C (closed squares) and 25 C (open squares) over a range of proteinconcentrations.

FIG. 48 is a chart demonstrating (Left) Initial and final (after heatingto 90° C. and then cooling to 20° C.) protein circular dichroismspectrum for SEQID-00105 and (Right) change in ellipticity at a givenwavelength over the temperature range for that SEQID-00105.

FIG. 49 is an image demonstrating Western blot analysis formannose-containing glycans. A) Coomassie-stained gel. B) GNA blottedmembrane. In both panels, lanes are as follows: 1) Pre-stained proteinladder, 2) SEQID-00363 (5 μg) from A. niger, 3) whole cell extract (5μg) from E. coli transformed with an expression vector encodingSEQID-00363, 4), GNA positive control carboxypeptidase (5 μg), 5)soluble lysate (5 μg) from E. coli transformed with an expression vectorencoding SEQID-00363.

FIG. 50 is an image demonstrating Western blot analysis for Neu5Gc. A)Coomassie-stained gel. B) anti-Neu5Gc probed membrane. In both panels,lanes are as follows: 1 & 10) Pre-stained protein ladder (New EnglandBiolab), 2& 11) beef extract (30 μg), 3) pork extract (30 μg), 4) deerextract (30 μg), 5) lamb extract (30 μg), 6) turkey extract (30 μg), 7)chicken extract (30 μg), 8) cod extract (30 μg), 9) Protein Mixture 1(10 μg), 12-15) 168 nutritive polypeptide library (30 μg) expressed in12) E. coli (IMAC-purified lysate), 13) B. subtilis (supernatant), 14)B. subtilis (lysate), 15) B. subtilis (IMAC-purified lysate), 16-20)cDNA Library (30 μg) expressed in 16) B. subtilis (PH951 Grac lysate),17) E. coli (Rosetta soluble lysate), 18) E. coli (Rosetta whole cell),19) E. coli (GamiB lysate), and 20) E. coli (Gami2 lysate).

FIG. 51 is an image demonstrating Western blot analysis for Xylose andFucose. A) Coomassie-stained gel. B) anti-Neu5Gc probed membrane. Inwestern blot analysis of samples of protein extracted from plants andfungi or recombinantly expressed by E. coli and A. niger, xylose- andfucose-containing glycans in A) Coomassie-stained gel. B)anti-NeuSGc-blotted membrane. In both panels, lanes are as follows: 1 &11) Pre-stained protein ladder (New England Biolab), 2) yeast extract(30 μg), 3) flaxseed extract (30 μg), 4) chicken extract (30 μg), 5)corn extract (30 μg), 6) potato extract (30 μg), 7) mushroom extract (30μg), 8) Protein Mixture 2 (30 μg), 9) HRP (2 μg), 10) fetuin (2 μg), 12)soy extract (30 μg), 13) rice extract (30 μg), 14) broccoli extract (30μg), 15) tomato extract (30 μg), 16) blueberry extract (30 μg), 17)grape extract (30 μg), 18) Protein Mixture 2 (30 μg), 19) HRP (2 μg),20) fetuin (2 μg).

FIG. 52 is a series of charts demonstrating change in average area underthe curve (AUC) (±SD) of plasma amino acid concentrations (M-h) measuredin blood samples collected from rats (n=2-4) over 4 h following oraladministration of the indicated nutritive polypeptides at the doseslisted in Table E33A. BCAA: branched chain amino acids, EAA: essentialamino acids.

FIG. 53 is a series of charts demonstrating average plasma amino acidconcentration (±SD)-time curve for rats (n=4) orally administered ofSEQID-00105 at 2.85 g/kg. BCAA: branched chain amino acids, EAA:essential amino acids.

FIG. 54 is a series of charts demonstrating dose-response effect ofSEQID-00105. (Left) Average plasma Leu concentration (±SD)-time curve(Right) Average area under the curve (AUC) (+SD) of plasma amino acidconcentrations (μh) measured in blood samples collected from rats (n=4)over 4 h following oral administration of SEQID-00105 at the doseslisted in Table E33A.

FIG. 55 is a series of charts demonstrating plasma amino acidconcentrations during rat pharmacokinetic studies of native and modifiedforms of SEQID-00363. Plasma amino acid profile of essential amino acids(EAAs) (A), Leucine (B), Serine (C), and Threonine (D) following oraladministration of saline (circle (), solid line) (n=4), nativeSEQID-00363 (square (▪), solid line) (n=4), deglycosylated SEQID-00363(open circle (◯), dashed line) (n=2), and hydrolyzed SEQID-00363 (opensquare (□), dashed line) (n=4). Data represent the mean±the standarddeviation of the mean for n=2-4 rats, as indicated above.

FIG. 56 is a series of charts demonstrating change in average FSR forWPI, SEQID-00105, and SEQID-363

FIG. 57 is a series of charts demonstrating human plasma time course ofmeasured amino acid s for WPI and SEQID-00105.

FIG. 58 is a series of charts demonstrating human plasma time course ofmeasured amino acid s for WPI and SEQID-00105.

FIG. 59 is a series of charts demonstrating human plasma time course ofmeasured amino acid s for WPI and SEQID-00105.

FIG. 60 is a series of charts demonstrating human plasma time course ofmeasured amino acid and the aggregate groups, essential amino acids(EAA), branched chain amino acids (BCAA), and total amino acids (TAA)for WPI and SEQID-00105.

FIG. 61 is a chart demonstrating integrated area under the curve (AUC)of measured amino acids, for WPI and SEQID-00105.

FIG. 62 is a chart demonstrating integrated area under the curve (AUC)of measured amino acids, for WPI and SEQID-00105.

FIG. 63 is a chart demonstrating integrated area under the curve (AUC)of aggregate groups, essential amino acids (EAA), branched chain aminoacids (BCAA), and total amino acids (TAA), for WPI and SEQID-00105.

FIG. 64 is a series of charts demonstrating human plasma time course ofmeasured amino acid s for WPI and SEQID-00105.

FIG. 65 is a series of charts demonstrating human plasma time course ofmeasured amino acid s for WPI and SEQID-00105.

FIG. 66 is a series of charts demonstrating human plasma time course ofmeasured amino acid s for WPI and SEQID-00105.

FIG. 67 is a series of charts demonstrating human plasma time course ofmeasured amino acid and the aggregate groups, essential amino acids(EAA), branched chain amino acids (BCAA), and total amino acids (TAA)for WPI and SEQID-00105.

FIG. 68 is a chart demonstrating integrated area under the curve (AUC)of measured amino acids, for WPI and SEQID-00105.

FIG. 69 is a chart demonstrating integrated area under the curve (AUC)of measured amino acids, for WPI and SEQID-00105.

FIG. 70 is a chart demonstrating integrated area under the curve (AUC)of aggregate groups, essential amino acids (EAA), branched chain aminoacids (BCAA), and total amino acids (TAA), for WPI and SEQID-00105

FIG. 71 is a series of charts demonstrating human plasma time course ofmeasured amino acid s for WPI and SEQID-00363.

FIG. 72 is a series of charts demonstrating human plasma time course ofmeasured amino acid s for WPI and SEQID-00363.

FIG. 73 is a series of charts demonstrating human plasma time course ofmeasured amino acid s for WPI and SEQID-00363.

FIG. 74 is a series of charts demonstrating human plasma time course ofmeasured amino acid and the aggregate groups, essential amino acids(EAA), branched chain amino acids (BCAA), and total amino acids (TAA)for WPI and SEQID-363.

FIG. 75 is a series of charts demonstrating human plasma time course ofmeasured amino acid s for WPI and SEQID-00426.

FIG. 76 is a series of charts demonstrating human plasma time course ofmeasured amino acid s for WPI and SEQID-00426.

FIG. 77 is a series of charts demonstrating human plasma time course ofmeasured amino acid s for WPI and SEQID-00426.

FIG. 78 is a series of charts demonstrating human plasma time course ofmeasured amino acid and the aggregate groups, essential amino acids(EAA), branched chain amino acids (BCAA), and total amino acids (TAA)for WPI and SEQID-00426.

DETAILED DESCRIPTION

Terms used in the claims and specification are defined as set forthbelow unless otherwise specified.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise.

DEFINITIONS

An “agriculturally-derived food product” is a food product resultingfrom the cultivation of soil or rearing of animals.

The term “ameliorating” refers to any therapeutically beneficial resultin the treatment of a disease state. e.g., including prophylaxis,lessening in the severity or progression, remission, or cure thereof.

As used herein, the term “autotrophic” refers to an organism thatproduces complex organic compounds (such as carbohydrates, fats, andproteins) from simple inorganic molecules using energy from light (byphotosynthesis) or inorganic chemical reactions (chemosynthesis).

As used herein, a “body mass index” or “BMI” or “Quetelet Index” is asubject's weight in kilograms divided by the square of the subject'sheight in meters (kg/m²). For adults, a frequent use of the BMI is toassess how much an individual's body weight departs from what is normalor desirable for a person of his or her height. The weight excess ordeficiency may, in part, be accounted for by body fat, although otherfactors such as muscularity also affect BMI significantly. The WorldHealth Organization regards a BMI of less than 18.5 as underweight andmay indicate malnutrition, an eating disorder, or other health problems,while a BMI greater than 25 is considered overweight and above 30 isconsidered obese. (World Health Organization. BMI classification).

As used herein, a “branched chain amino acid” is an amino acid selectedfrom Leucine. Isoleucine, and Valine.

As used herein, “cachexia” refers to a multifaceted clinical syndromethat results in muscle wasting and weight loss. It is a complexcondition where protein catabolism exceeds protein anabolism, whichmakes muscle wasting a primary feature of the condition. In addition tothe metabolic derangements in protein metabolism, it is alsocharacterized by anorexia and inflammation. These derangements plusimpaired protein metabolism are responsive to nutrition therapy tovarying degrees.

As used herein, “calorie control” and “calorie restriction” refer to theprocess of reducing a subject's calorie intake from food products,either relative to the subject's prior calorie intake or relative to anappropriate calorie intake standard.

Generally, the terms “cancer” and “cancerous” refer to or describe thephysiological condition in mammals that is typically characterized byunregulated cell growth. More specifically, cancers that are treatedusing any one or more tyrosine kinase inhibitors, other drugs blockingthe receptors or their ligands, or variants thereof, and in connectionwith the methods provided herein include, but are not limited to,carcinoma, lymphoma, blastoma, sarcoma, leukemia, mesothelioma, squamouscell cancer, lung cancer including small-cell lung cancer and non-smallcell lung cancer (which includes large-cell carcinoma, adenocarcinoma ofthe lung, and squamous carcinoma of the lung), cancer of the peritoneum,hepatocellular cancer, gastric or stomach cancer (includinggastrointestinal cancer and gastrointestinal stromal cancer), pancreaticcancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer,bladder cancer, breast cancer, colon cancer, colorectal cancer,endometrial or uterine carcinoma, salivary gland carcinoma, kidney orrenal cancer, prostate cancer, cervical cancer, vulval cancer, thyroidcancer, head and neck cancer, melanoma, superficial spreading melanoma,lentigo maligna melanoma, acral lentiginous melanomas, nodularmelanomas, T-cell lymphomas, B-cell lymphomas (including lowgrade/follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL)NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL;high grade immunoblastic NHL; high grade lymphoblastic NHL; high gradesmall non-cleaved cell NHL: bulky disease NHL: mantle cell lymphoma;AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia); chroniclymphocytic leukemia (CLL); acute myeloid leukemia (AML); chronicmyeloid leukemia (CML); acute lymphoblastic leukemia (ALL); Hairy cellleukemia; chronic myeloblastic leukemia; or post-transplantlymphoproliferative disorder (PTLD), as well as abnormal vascularproliferation associated with phakomatoses, edema (such as thatassociated with brain tumors), and Meigs' syndrome.

A “comestible product” includes an edible product, while a“non-comestible product” is generally an inedible product or contains aninedible product. To be “substantially free of non-comestible products”means a composition does not have an amount or level of non-comestibleproduct sufficient to render the composition inedible, dangerous orotherwise unfit for consumption by its intended consumer. Alternatively,a polypeptide can be substantially free of non-comestible products,meaning the polypeptide does not contain or have associated therewith anamount or level of non-comestible product sufficient to render acomposition containing the polypeptide inedible by, or unsafe ordeleterious to, its intended consumer. In preferred embodiments acomposition substantially free of non-comestible products can beconsumed in a nutritional amount by an intended consumer who does notsuffer or is not at increased risk of suffering a deleterious event fromsuch consumption. For example, levels of lead and other metals arewell-documented as having significant risk including toxicity to humanswhen present in food, particularly foods containing anagriculturally-derived product grown in soil contaminated with leadand/or other metals. Thus, products such as foods, beverages, andcompounds containing industrially-produced polypeptides having metalcontent above a certain parts per million (ppm), are considerednon-comestible products, such metal content depending upon the metal asrecognized in the art. For example, inclusion of lead or cadmium in anindustrially-produced polypeptide at levels such that the lead will havea deleterious biological effect when consumed by a mammal will generallyrender a composition containing the industrially-produced polypeptidenon-comestible. Notwithstanding the above, some polypeptides havecertain amounts of metals complexed to or incorporated therein (such asiron, zinc, calcium and magnesium) and such metals shall not necessarilyrender the polypeptides non-comestible.

The term “control sequences” is intended to encompass, at a minimum, anycomponent whose presence is essential for expression, and can alsoencompass an additional component whose presence is advantageous, forexample, leader sequences and fusion partner sequences.

As used herein, a patient is “critically-medically ill” if the patient,because of medical illness, experiences changes in at least one of bodymass index and muscle mass (e.g., sarcopenia). In some embodiments thepatient is confined to bed for at least 25%, at least 50%, at least 60%,at least 70%, at least 80%, at least 90%, at least 95%, or 100% of theirwaking time. In some embodiments the patient is unconscious. In someembodiments the patient has been confined to bed as described in thisparagraph for at least 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 2weeks, 3 weeks, 4 weeks, 5 weeks, 10 weeks or longer.

As used herein, the phrase “degenerate variant” of a reference nucleicacid sequence encompasses nucleic acid sequences that can be translated,according to the standard genetic code, to provide an amino acidsequence identical to that translated from the reference nucleic acidsequence. The term “degenerate oligonucleotide” or “degenerate primer”is used to signify an oligonucleotide capable of hybridizing with targetnucleic acid sequences that are not necessarily identical in sequencebut that are homologous to one another within one or more particularsegments.

As used herein a “desirable body mass Index” is a body mass index offrom about 18.5 to about 25. Thus, if a subject has a BMI below about18.5, then an increase in the subject's BMI is an increase in thedesirability of the subject's BMI. If instead a subject has a BMI aboveabout 25, then a decrease in the subject's BMI is an increase in thedesirability of the subject's BMI.

As used herein, the term “diabetes” includes any metabolic disease inwhich a subject is unable to produce any or a sufficient amount ofinsulin or is otherwise unable to regulate blood glucose level. The term“pre-diabetes” is also termed “impaired fasting glucose” includes acondition in which fasting glucose is above an accepted normal limit

As used herein, an “elderly” mammal is one who experiences age relatedchanges in at least one of body mass index and muscle mass (e.g., agerelated sarcopenia). In some embodiments an “elderly” human is at least50 years old, at least 60 years old, at least 65 years old, at least 70years old, at least 75 years old, at least 80 years old, at least 85years old, at least 90 years old, at least 95 years old, or at least 100years old. In some embodiments and an elderly animal, mammal, or humanis a human who has experienced a loss of muscle mass from peak lifetimemuscle mass of at least 5%, at least 10%, at least 15%, at least 20%, atleast 25%, at least 30%, at least 35%, at least 40%, at least 45%, atleast 50%, at least 55%, or at least 60%. Because age related changes toat least one of body mass index and muscle mass are known to correlatewith increasing age, in some embodiments an elderly mammal is identifiedor defined simply on the basis of age. Thus, in some embodiments an“elderly” human is identified or defined simply by the fact that theirage is at least 60 years old, at least 65 years old, at least 70 yearsold, at least 75 years old, at least 80 years old, at least 85 yearsold, at least 90 years old, at least 95 years old, or at least 100 yearsold, and without recourse to a measurement of at least one of body massindex and muscle mass.

As used herein, an “essential amino acid” is an amino acid selected fromHistidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine,Threonine, Tryptophan, and Valine. However, it should be understood that“essential amino acids” can vary through a typical lifespan, e.g.,cysteine, tyrosine, and arginine are considered essential amino acids ininfant humans. Imura K, Okada A (1998). “Amino acid metabolism inpediatric patients”. Nutrition 14 (1): 143-8. In addition, the aminoacids arginine, cysteine, glycine, glutamine, histidine, proline, serineand tyrosine are considered “conditionally essential” in adults, meaningthey are not normally required in the diet, but must be suppliedexogenously to specific populations that do not synthesize them inadequate amounts. Fürst P, Stehle P (1 Jun. 2004). “What are theessential elements needed for the determination of amino acidrequirements in humans?”. Journal of Nutrition 134 (6 Suppl):1558S-1565S; and Reeds P J (1 Jul. 2000). “Dispensable and indispensableamino acids for humans”. J. Nutr, 130 (7): 1835S-40S.

As used herein, “exercise” is, most broadly, any bodily activity thatenhances or maintains physical fitness and overall health and wellness.Exercise is performed for various reasons including strengtheningmuscles and the cardiovascular system, honing athletic skills, weightloss or maintenance, as well as for the purpose of enjoyment.

As used herein, an “exercise regimen” includes any course of exercisefor the promotion of health, or for the treatment or prevention ofdisease.

As used herein, an “expression control sequence” refers topolynucleotide sequences which are necessary to affect the expression ofcoding sequences to which they are operatively linked. Expressioncontrol sequences are sequences which control the transcription,post-transcriptional events and translation of nucleic acid sequences.Expression control sequences include appropriate transcriptioninitiation, termination, promoter and enhancer sequences; efficient RNAprocessing signals such as splicing and polyadenylation signals;sequences that stabilize cytoplasmic mRNA; sequences that enhancetranslation efficiency (e.g., ribosome binding sites); sequences thatenhance protein stability; and when desired, sequences that enhanceprotein secretion. The nature of such control sequences differsdepending upon the host organism; in prokaryotes, such control sequencesgenerally include promoter, ribosomal binding site, and transcriptiontermination sequence.

As used herein, “function” and “functional performance” refers to afunctional test that simulates daily activities. “Muscle function” or“functional performance” is measured by any suitable accepted test,including timed-step test (step up and down from a 4 inch bench as fastas possible 5 times), timed floor transfer test (go from a standingposition to a supine position on the floor and thereafter up to astanding position again as fast as possible for one repetition), andphysical performance battery test (static balance test, chair test, anda walking test) (Borsheim et al., “Effect of amino acid supplementationon muscle mass, strength and physical function in elderly,” Clin Nutr2008; 27: 189-195). As used herein, a “performance-associated” injury ordamage, such as a tissue injury or tissue damage, results from afunctional activity, such as a physical or athletic performance.

The term “fusion protein” refers to a polypeptide comprising apolypeptide or fragment coupled to heterologous amino acid sequences.Fusion proteins are useful because they can be constructed to containtwo or more desired functional elements that can be from two or moredifferent proteins. A fusion protein comprises at least 10 contiguousamino acids from a polypeptide of interest, or at least 20 or 30 aminoacids, or at least 40, 50 or 60 amino acids, or at least 75, 100 or 125amino acids. The heterologous polypeptide included within the fusionprotein is usually at least 6 amino acids in length, or at least 8 aminoacids in length, or at least 15, 20, or 25 amino acids in length.Fusions that include larger polypeptides, such as an IgG Fc region, andeven entire proteins, such as the green fluorescent protein (“GFP”)chromophore-containing proteins, have particular utility. Fusionproteins can be produced recombinantly by constructing a nucleic acidsequence which encodes the polypeptide or a fragment thereof in framewith a nucleic acid sequence encoding a different protein or peptide andthen expressing the fusion protein. Alternatively, a fusion protein canbe produced chemically by crosslinking the polypeptide or a fragmentthereof to another protein.

Sequence homology for polypeptides, which is also referred to as percentsequence identity, is typically measured using sequence analysissoftware. See, e.g., the Sequence Analysis Software Package of theGenetics Computer Group (GCG), University of Wisconsin BiotechnologyCenter, 910 University Avenue, Madison, Wis. 53705. Protein analysissoftware matches similar sequences using a measure of homology assignedto various substitutions, deletions and other modifications, includingconservative amino acid substitutions. For instance, (CG containsprograms such as “Gap” and “Bestfit” which can be used with defaultparameters to determine sequence homology or sequence identity betweenclosely related polypeptides, such as homologous polypeptides fromdifferent species of organisms or between a wild-type polypeptide and amutein thereof. See, e.g., GCG Version 6. An exemplary algorithm whencomparing a particular polypeptide sequence to a database containing alarge number of sequences from different organisms is the computerprogram BLAST (Altschul et al., J. Mol. Biol. 215:403-410 (1990); Gishand States, Nature Genet. 3:266-272 (1993); Madden et al., Meth.Enzymol. 266:131-141 (1996); Altschul et al., Nucleic Acids Res.25:3389-3402 (1997): Zhang and Madden, Genome Res. 7:649-656 (1997)),especially blastp or tblastn (Altschul et al., Nucleic Acids Res.25:3389-3402 (1997)).

As used herein, a “gastrointestinal disorder” or a “gastrointestinaldisease” includes any disorder or disease involving the gastrointestinaltract or region thereof, namely the esophagus, stomach, small intestine,large intestine or rectum, as well as organs and tissues associated withdigestion, e.g., the pancreas, the gallbladder, and the liver.

As used herein, the term “heterotrophic” refers to an organism thatcannot fix carbon and uses organic carbon for growth.

As used herein, a polypeptide has “homology” or is “homologous” to asecond polypeptide if the nucleic acid sequence that encodes thepolypeptide has a similar sequence to the nucleic acid sequence thatencodes the second polypeptide. Alternatively, a polypeptide hashomology to a second polypeptide if the two polypeptides have similaramino acid sequences. (Thus, the term “homologous polypeptides” isdefined to mean that the two polypeptides have similar amino acidsequences.) When “homologous” is used in reference to polypeptides orpeptides, it is recognized that residue positions that are not identicaloften differ by conservative amino acid substitutions. A “conservativeamino acid substitution” is one in which an amino acid residue issubstituted by another amino acid residue having a side chain (R group)with similar chemical properties (e.g., charge or hydrophobicity). Ingeneral, a conservative amino acid substitution will not substantiallychange the functional properties of a polypeptide. In cases where two ormore amino acid sequences differ from each other by conservativesubstitutions, the percent sequence identity or degree of homology canbe adjusted upwards to correct for the conservative nature of thesubstitution. Means for making this adjustment are well known to thoseof skill in the art. See, e.g., Pearson, 1994, Methods Mol. Biol.24:307-31 and 25:365-89. The following six groups each contain aminoacids that are conservative substitutions for one another: 1) Serine,Threonine; 2) Aspartic Acid. Glutamic Acid; 3) Asparagine, Glutamine; 4)Arginine, Lysine; 5) Isoleucine, Leucine, Methionine, Alanine, Valine,and 6) Phenylalanine. Tyrosine. Tryptophan. In some embodiments,polymeric molecules (e.g., a polypeptide sequence or nucleic acidsequence) are considered to be homologous to one another if theirsequences are at least 25%, at least 30%, at least 35%, at least 40%, atleast 45%, at least 50%, at least 55%, at least 60%, at least 65%, atleast 70%, at least 75%, at least 80%, at least 85%, at least 90%, atleast 95%, at least 96%, %, at least 97%, %, at least 98%, or at least99% identical. In some embodiments, polymeric molecules are consideredto be “homologous” to one another if their sequences are at least 25%,at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90%, at least 95%, at least 96%, %, atleast 97%, %, at least 98%, or at least 99% similar. The term“homologous” necessarily refers to a comparison between at least twosequences (nucleotides sequences or amino acid sequences). In someembodiments, two nucleotide sequences are considered to be homologous ifthe polypeptides they encode are at least about 50% identical, at leastabout 60% identical at least about 70% identical, at least about 80%identical, or at least about 90% identical for at least one stretch ofat least about 10, 15, 20, 25, 30, 35, 40, 45, 50 or over 50 aminoacids. In some embodiments, homologous nucleotide sequences arecharacterized by the ability to encode a stretch of at least 4-5uniquely specified amino acids. Both the identity and the approximatespacing of these amino acids relative to one another must be consideredfor nucleotide sequences to be considered homologous. In someembodiments of nucleotide sequences less than 60 nucleotides in length,homology is determined by the ability to encode a stretch of at least4-5 uniquely specified amino acids. In some embodiments, two polypeptidesequences are considered to be homologous if the polypeptides are atleast about 50% identical, at least about 60% identical, at least about70% identical, at least about 80% identical, or at least about 90%identical for at least one stretch of at least about 20 amino acids. Inother embodiments, two polypeptide sequences are considered to behomologous if the polypeptides are similar, such as at least about 50%similar, at least about 60% similar, at least about 70% similar, atleast about 80% similar, or at least about 90% similar, or at leastabout 95% similar for at least one stretch of at least about 20 aminoacids. In some embodiments similarity is demonstrated by fewernucleotide changes that result in an amino acid change (e.g., a nucleicacid sequence having a single nucleotide change is more similar to areference nucleic acid sequence than a nucleic acid sequence having twonucleotide changes, even if both changes result in an identical aminoacid substitution.

The term “in situ” refers to processes that occur in a living cellgrowing separate from a living organism, e.g., growing in tissueculture.

As used herein, the term “in vitro” refers to events that occur in anartificial environment. e.g., in a test tube or reaction vessel, in cellculture, in a Petri dish, etc., rather than within an organism (e.g.,animal, plant, or microbe). As used herein, the term “ex vivo” refers toexperimentation done in or on tissue in an environment outside theorganism.

The term “in vivo” refers to processes that occur in a living organism.

As used herein, a “modified derivative” refers to polypeptides orfragments thereof that are substantially homologous in primarystructural sequence to a reference polypeptide sequence but whichinclude, e.g., in vivo or in vitro chemical and biochemicalmodifications or which incorporate amino acids that are not found in thereference polypeptide. Such modifications include, for example,acetylation, carboxylation, phosphorylation, glycosylation,ubiquitination, labeling, e.g., with radionuclides, and variousenzymatic modifications, as will be readily appreciated by those skilledin the art. A variety of methods for labeling polypeptides and ofsubstituents or labels useful for such purposes are well known in theart, and include radioactive isotopes such as 125I, 32P, 35S, and 3H,ligands that bind to labeled antiligands (e.g., antibodies),fluorophores, chemiluminescent agents, enzymes, and antiligands that canserve as specific binding pair members for a labeled ligand. The choiceof label depends on the sensitivity required, ease of conjugation withthe primer, stability requirements, and available instrumentation.Methods for labeling polypeptides are well known in the art. See, e.g.,Ausubel et al., Current Protocols in Molecular Biology, GreenePublishing Associates (1992, and Supplements to 2002).

As used herein, “muscle strength” refers to the amount of force a musclecan produce with a single maximal effort. There are two types of musclestrength, static strength and dynamic strength. Static strength refersto isometric contraction of a muscle, where a muscle generates forcewhile the muscle length remains constant and/or when there is nomovement in a joint. Examples include holding or carrying an object, orpushing against a wall. Dynamic strength refers to a muscle generatingforce that results in movement. Dynamic strength can be isotoniccontraction, where the muscle shortens under a constant load orisokinetic contraction, where the muscle contracts and shortens at aconstant speed. Dynamic strength can also include isoinertial strength.In addition, the term “muscle strength” refers to maximum dynamic musclestrength, as described by the term “one repetition maximum” (1RM). Thisis a measurement of the greatest load (in kilograms) that can be fullymoved (lifted, pushed or pulled) once without failure or injury. Thisvalue can be measured directly, but doing so requires that the weight isincreased until the subject fails to carry out the activity tocompletion. Alternatively, 1RM is estimated by counting the maximumnumber of exercise repetitions a subject can make using a load that isless than the maximum amount the subject can move. Leg extension and legflexion are often measured in clinical trials (Borsheim et al., “Effectof amino acid supplementation on muscle mass, strength and physicalfunction in elderly,” Clin Nutr 2008; 27:189-195; Paddon-Jones, et al.,“Essential amino acid and carbohydrate supplementation amelioratesmuscle protein loss in humans during 28 days bed rest,” J ClinEndocrinol Metab 2004; 89:4351-4358).

As used herein, “muscle mass” refers to the weight of muscle in asubject's body. Similarly, “muscle anabolism” includes the synthesis ofmuscle proteins, and is a component of the process by which muscle massis gained. Muscle mass includes the skeletal muscles, smooth muscles(such as cardiac and digestive muscles) and the water contained in thesemuscles. Muscle mass of specific muscles can be determined using dualenergy x-ray absorptiometry (DEXA) (Padden-Jones et al., 2004). Totallean body mass (minus the fat), total body mass, and bone mineralcontent can be measured by DEXA as well. In some embodiments a change inthe muscle mass of a specific muscle of a subject is determined, forexample by DEXA, and the change is used as a proxy for the total changein muscle mass of the subject. Thus, for example, if a subject consumesa nutritive protein as disclosed herein and experiences an increase overa period of time in muscle mass in a particular muscle or muscle group,it can be concluded that the subject has experienced an increase inmuscle mass. Changes in muscle mass can be measured in a variety of waysincluding protein synthesis, fractional synthetic rate, and certain keyactivities such mTor/mTorc. In general, “lean muscle mass” refers to themass of muscle tissue in the absence of other tissues such as fat.

The term “nucleic acid fragment” as used herein refers to a nucleic acidsequence that has a deletion, e.g., a 5′-terminal or 3′-terminaldeletion compared to a full-length reference nucleotide sequence. In anembodiment, the nucleic acid fragment is a contiguous sequence in whichthe nucleotide sequence of the fragment is identical to thecorresponding positions in the naturally-occurring sequence. In someembodiments, fragments are at least 10, 15, 20, or 25 nucleotides long,or at least 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or150 nucleotides long. In some embodiments a fragment of a nucleic acidsequence is a fragment of an open reading frame sequence. In someembodiments such a fragment encodes a polypeptide fragment (as definedherein) of the protein encoded by the open reading frame nucleotidesequence.

A composition, formulation or product is “nutritional” or “nutritive” ifit provides an appreciable amount of nourishment to its intendedconsumer, meaning the consumer assimilates all or a portion of thecomposition or formulation into a cell, organ, and/or tissue. Generallysuch assimilation into a cell, organ and/or tissue provides a benefit orutility to the consumer. e.g., by maintaining or improving the healthand/or natural function(s) of said cell, organ, and/or tissue. Anutritional composition or formulation that is assimilated as describedherein is termed “nutrition.” By way of non-limiting example, apolypeptide is nutritional if it provides an appreciable amount ofpolypeptide nourishment to its intended consumer, meaning the consumerassimilates all or a portion of the protein, typically in the form ofsingle amino acids or small peptides, into a cell, organ, and/or tissue.“Nutrition” also means the process of providing to a subject, such as ahuman or other mammal, a nutritional composition, formulation, productor other material. A nutritional product need not be “nutritionallycomplete,” meaning if consumed in sufficient quantity, the productprovides all carbohydrates, lipids, essential fatty acids, essentialamino acids, conditionally essential amino acids, vitamins, and mineralsrequired for health of the consumer. Additionally, a “nutritionallycomplete protein” contains all protein nutrition required (meaning theamount required for physiological normalcy by the organism) but does notnecessarily contain micronutrients such as vitamins and minerals,carbohydrates or lipids.

In preferred embodiments, a composition or formulation is nutritional inits provision of polypeptide capable of decomposition (i.e., thebreaking of a peptide bond, often termed protein digestion) to singleamino acids and/or small peptides (e.g., two amino acids, three aminoacids, or four amino acids, possibly up to ten amino acids) in an amountsufficient to provide a “nutritional benefit.” In addition, in certainembodiments provided are nutritional polypeptides that transit acrossthe gastrointestinal wall and are absorbed into the bloodstream as smallpeptides (e.g., larger than single amino acids but smaller than aboutten amino acids) or larger peptides, oligopeptides or polypeptides(e.g., >11 amino acids). A nutritional benefit in apolypeptide-containing composition can be demonstrated and, optionally,quantified, by a number of metrics. For example, a nutritional benefitis the benefit to a consuming organism equivalent to or greater than atleast about 0.5% of a reference daily intake value of protein, such asabout 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% or greaterthan about 100% of a reference daily intake value. Alternatively, anutritional benefit is demonstrated by the feeling and/or recognition ofsatiety by the consumer. In other embodiments, a nutritional benefit isdemonstrated by incorporation of a substantial amount of the polypeptidecomponent of the composition or formulation into the cells, organsand/or tissues of the consumer, such incorporation generally meaningthat single amino acids or short peptides are used to producepolypeptides de novo intracellularly. A “consumer” or a “consumingorganism” means any animal capable of ingesting the product having thenutritional benefit. Typically, the consumer will be a mammal such as ahealthy human, e.g., a healthy infant, child, adult, or older adult.Alternatively, the consumer will be a mammal such as a human (e.g., aninfant, child, adult or older adult) at risk of developing or sufferingfrom a disease, disorder or condition characterized by (i) the lack ofadequate nutrition and/or (ii) the alleviation thereof by thenutritional products of the present invention. An “infant” is generallya human under about age 1 or 2, a “child” is generally a human underabout age 18, and an “older adult” or “elderly” human is a human agedabout 65 or older.

In other preferred embodiments, a composition or formulation isnutritional in its provision of carbohydrate capable of hydrolysis bythe intended consumer (termed a “nutritional carbohydrate”). Anutritional benefit in a carbohydrate-containing composition can bedemonstrated and, optionally, quantified, by a number of metrics. Forexample, a nutritional benefit is the benefit to a consuming organismequivalent to or greater than at least about 2% of a reference dailyintake value of carbohydrate.

A polypeptide “nutritional domain” as used herein means any domain of apolypeptide that is capable of providing nutrition. Preferably, apolypeptide nutritional domain provides one or more advantages over thefull-length polypeptide containing the nutritional domain, such as thenutritional domain provides more nutrition than the full-lengthpolypeptide. For example, a polypeptide nutritional domain has a higherconcentration of desirable amino acids, has a lower concentration ofundesirable amino acids, contains a site for cleavage by a digestiveprotease, is easier to digest and/or is easier to produce from thedigestion of a larger polypeptide, has improved storage characteristics,or a combination of these and/or other factors, in comparison to (i) areference polypeptide or a reference polypeptide-containing mixture orcomposition, (ii) the protein(s) or polypeptide(s) present in anagriculturally-derived food product, and/or (iii) the protein orpolypeptide products present in the diet of a mammalian subject. Otheradvantages of a polypeptide nutritional domain includes easier and/ormore efficient production, different or more advantageous physiochemicalproperties, and/or has different s or more advantageous safetyproperties (e.g., elimination of one or more allergy domains) relativeto full-length polypeptide. A reference polypeptide can be a naturallyoccurring polypeptide or a recombinantly produced polypeptide, which inturn may have an amino acid sequence identical to or different from anaturally occurring polypeptide. A reference polypeptide may also be aconsensus amino acid sequence not present in a naturally-occurringpolypeptide. Additionally, a reference polypeptide-containing mixture orcomposition can be a naturally-occurring mixture, such as a mixture ofpolypeptides present in a dairy product such as milk or whey, or can bea synthetic mixture of polypeptides (which, in turn, can benaturally-occurring or synthetic). In certain embodiments thenutritional domain contains an amino acid sequence having an N-terminalamino acid and/or a C-terminal amino acid different from the N-terminalamino acid and/or a C-terminal amino acid of a reference secretedpolypeptide, such as a full-length secreted polypeptide. For example, anutritional domain has an N-terminal amino acid sequence thatcorresponds to an amino acid sequence internal to a larger secretedpolypeptide that contains the nutritional domain. A nutritional domainmay include or exclude a signal sequence of a larger secretedpolypeptide. As used herein, a polypeptide that “contains” a polypeptidenutritional domain contains the entirety of the polypeptide nutritionaldomain as well as at least one additional amino acid, either N-terminalor C-terminal to the polypeptide nutritional domain. Generallypolypeptide nutritional domains are secreted from the cell or organismcontaining a nucleic acid encoding the nutritional domain, and aretermed “secreted polypeptide nutritional domains.” and, in circumstanceswherein the nutritional domain is secreted from a unicellular (or singlecelled) organism, it is termed a “unicellular secreted polypeptidenutritional domain.”

In other preferred embodiments, a composition or formulation isnutritional in its provision of lipid capable of digestion,incorporation, conversion, or other cellular uses by the intendedconsumer (termed a “nutritional lipid”). A nutritional benefit in alipid-containing composition can be demonstrated and, optionally,quantified, by a number of metrics. For example, a nutritional benefitis the benefit to a consuming organism equivalent to or greater than atleast about 2% of a reference daily intake value of lipid (i.e., fat).

As used herein, an “obese” subject has a level of excess body fat that,increasing the likelihood of the subject suffering from diseasesincluding heart disease, type II diabetes, osteoporosis andosteoarthritis, and cancer, while an “overweight” subject is above aweight recognized as normal, acceptable, or desirable, but not obese. InWestern countries, a subject having a BMI value exceeding 30 isconsidered obese, while a subject having a BMI value between 25-30 isconsidered overweight.

As used herein, “operatively linked” or “operably linked” expressioncontrol sequences refers to a linkage in which the expression controlsequence is contiguous with the gene of interest to control the gene ofinterest, as well as expression control sequences that act in trans orat a distance to control the gene of interest.

The term “percent sequence identity” or “identical” in the context ofnucleic acid sequences refers to the residues in the two sequences thatare the same when aligned for maximum correspondence. There are a numberof different algorithms known in the art that can be used to measurenucleotide sequence identity. For instance, polynucleotide sequences canbe compared using FASTA, Gap or Bestfit, which are programs in WisconsinPackage Version 10.0, Genetics Computer Group (GCG), Madison, Wis. FASTAprovides alignments and percent sequence identity of the regions of thebest overlap between the query and search sequences. Pearson. MethodsEnzymol. 183:63-98 (1990).

The term “polynucleotide,” “nucleic acid molecule,” “nucleic acid,” or“nucleic acid sequence” refers to a polymeric form of nucleotides of atleast 10 bases in length. The term includes DNA molecules (e.g., cDNA orgenomic or synthetic DNA) and RNA molecules (e.g., mRNA or syntheticRNA), as well as analogs of DNA or RNA containing non-natural nucleotideanalogs, non-native internucleoside bonds, or both. The nucleic acid canbe in any topological conformation. For instance, the nucleic acid canbe single-stranded, double-stranded, triple-stranded, quadruplexed,partially double-stranded, branched, hairpinned, circular, or in apadlocked conformation. A “synthetic” RNA, DNA or a mixed polymer is onecreated outside of a cell, for example one synthesized chemically. Theterm “nucleic acid fragment” as used herein refers to a nucleic acidsequence that has a deletion, e.g., a 5′-terminal or 3′-terminaldeletion of one or more nucleotides compared to a full-length referencenucleotide sequence. In an embodiment, the nucleic acid fragment is acontiguous sequence in which the nucleotide sequence of the fragment isidentical to the corresponding positions in the naturally-occurringsequence. In some embodiments, fragments are at least 10, 15, 20, or 25nucleotides long, or at least 20, 30, 40, 50, 60, 70, 80, 90, 100, 110,120, 130, 140, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650,700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600,1700, 1800 or greater than 1800 nucleotides long. In some embodiments afragment of a nucleic acid sequence is a fragment of an open readingframe sequence. In some embodiments such a fragment encodes apolypeptide fragment (as defined herein) of the polypeptide encoded bythe open reading frame nucleotide sequence.

The terms “polypeptide” and “protein” can be interchanged, and theseterms encompass both naturally-occurring and non-naturally occurringpolypeptides, and, as provided herein or as generally known in the art,fragments, mutants, derivatives and analogs thereof. A polypeptide canbe monomeric, meaning it has a single chain, or polymeric, meaning it iscomposed of two or more chains, which can be covalently ornon-covalently associated. Further, a polypeptide may comprise a numberof different domains each of which has one or more distinct activities.For the avoidance of doubt, a polypeptide can be any length greater thanor equal to two amino acids. The term “isolated polypeptide” is apolypeptide that by virtue of its origin or source of derivation (1) isnot associated with naturally associated components that accompany it inany of its native states, (2) exists in a purity not found in nature,where purity can be adjudged with respect to the presence of othercellular material (e.g., is free of other polypeptides from the samespecies or from the host species in which the polypeptide was produced)(3) is expressed by a cell from a different species, (4) isrecombinantly expressed by a cell (e.g., a polypeptide is an “isolatedpolypeptide” if it is produced from a recombinant nucleic acid presentin a host cell and separated from the producing host cell, (5) does notoccur in nature (e.g., it is a domain or other fragment of a polypeptidefound in nature or it includes amino acid analogs or derivatives notfound in nature or linkages other than standard peptide bonds), or (6)is otherwise produced, prepared, and/or manufactured by the hand of man.Thus, an “isolated polypeptide” includes a polypeptide that is producedin a host cell from a recombinant nucleic acid (such as a vector),regardless of whether the host cell naturally produces a polypeptidehaving an identical amino acid sequence. A “polypeptide” includes apolypeptide that is produced by a host cell via overexpression, e.g.,homologous overexpression of the polypeptide from the host cell such asby altering the promoter of the polypeptide to increase its expressionto a level above its normal expression level in the host cell in theabsence of the altered promoter. A polypeptide that is chemicallysynthesized or synthesized in a cellular system different from a cellfrom which it naturally originates will be “isolated” from its naturallyassociated components. A polypeptide may also be rendered substantiallyfree of naturally associated components by isolation, using proteinpurification techniques well known in the art. As thus defined,“isolated” does not necessarily require that the protein, polypeptide,peptide or oligopeptide so described has been physically removed from acell in which it was synthesized.

The term “polypeptide fragment” or “protein fragment” as used hereinrefers to a polypeptide or domain thereof that has less amino acidscompared to a reference polypeptide, e.g., a full-length polypeptide ora polypeptide domain of a naturally occurring protein. A “naturallyoccurring protein” or “naturally occurring polypeptide” includes apolypeptide having an amino acid sequence produced by a non-recombinantcell or organism. In an embodiment, the polypeptide fragment is acontiguous sequence in which the amino acid sequence of the fragment isidentical to the corresponding positions in the naturally-occurringsequence. Fragments typically are at least 5, 6, 7, 8, 9 or 10 aminoacids long, or at least 12, 14, 16 or 18 amino acids long, or at least20 amino acids long, or at least 25, 30, 35, 40 or 45, amino acids, orat least 50, 60, 70, 80, 90 or 100 amino acids long, or at least 110,120, 130, 140, 150, 160, 170, 180, 190 or 200 amino acids long, or 225,250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575,600 or greater than 600 amino acids long. A fragment can be a portion ofa larger polypeptide sequence that is digested inside or outside thecell. Thus, a polypeptide that is 50 amino acids in length can beproduced intracellularly, but proteolyzed inside or outside the cell toproduce a polypeptide less than 50 amino acids in length. This is ofparticular significance for polypeptides shorter than about 25 aminoacids, which can be more difficult than larger polypeptides to producerecombinantly or to purify once produced recombinantly. The term“peptide” as used herein refers to a short polypeptide or oligopeptide,e.g., one that typically contains less than about 50 amino acids andmore typically less than about 30 amino acids, or more typically lessthan about 15 amino acids, such as less than about 10, 9, 8, 7, 6, 5, 4,or 3 amino acids. The term as used herein encompasses analogs andmimetics that mimic structural and thus biological function.

As used herein, “polypeptide mutant” or “mutein” refers to a polypeptidewhose sequence contains an insertion, duplication, deletion,rearrangement or substitution of one or more amino acids compared to theamino acid sequence of a reference protein or polypeptide, such as anative or wild-type protein. A mutein may have one or more amino acidpoint substitutions, in which a single amino acid at a position has beenchanged to another amino acid, one or more insertions and/or deletions,in which one or more amino acids are inserted or deleted, respectively,in the sequence of the reference protein, and/or truncations of theamino acid sequence at either or both the amino or carboxy termini. Amutein may have the same or a different biological activity compared tothe reference protein. In some embodiments, a mutein has, for example,at least 85% overall sequence homology to its counterpart referenceprotein. In some embodiments, a mutein has at least 90% overall sequencehomology to the wild-type protein. In other embodiments, a muteinexhibits at least 95% sequence identity, or 98%, or 99%, or 99.5% or99.9% overall sequence identity.

As used herein, a “polypeptide tag for affinity purification” is anypolypeptide that has a binding partner that can be used to isolate orpurify a second protein or polypeptide sequence of interest fused to thefirst “tag” polypeptide. Several examples are well known in the art andinclude a His-6 tag, a FLAG epitope, a c-myc epitope, a Strep-TAGII, abiotin tag, a glutathione 5-transferase (GST), a chitin binding protein(CBP), a maltose binding protein (MBP), or a metal affinity tag.

As used herein, “protein-energy malnutrition” refers to a form ofmalnutrition where there is inadequate protein intake. Types includeKwashiorkor (protein malnutrition predominant), Marasmus (deficiency inboth calorie and protein nutrition), and Marasmic Kwashiorkor (markedprotein deficiency and marked calorie insufficiency signs present,sometimes referred to as the most severe form of malnutrition).“Malnourishment” and “malnutrition” are used equivalently herein.

The terms “purify,” “purifying” and “purified” refer to a substance (orentity, composition, product or material) that has been separated fromat least some of the components with which it was associated either wheninitially produced (whether in nature or in an experimental setting), orduring any time after its initial production. A substance such as anutritional polypeptide will be considered purified if it is isolated atproduction, or at any level or stage up to and including a finalproduct, but a final product may contain other materials up to about10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%,about 80%, about 90%, or above about 90% and still be considered“isolated.” Purified substances or entities can be separated from atleast about 10%, about 20%, about 30%, about 40%, about 50%, about 60%,about 70%, about 80%, about 90%, or more of the other components withwhich they were initially associated. In some embodiments, purifiedsubstances are more than about 80%, about 85%, about 90%, about 91%,about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about98%, about 99%, or more than about 99% pure. In the instance ofpolypeptides and other polypeptides provided herein, such a polypeptidecan be purified from one or more other polypeptides capable of beingsecreted from the unicellular organism that secretes the polypeptide. Asused herein, a polypeptide substance is “pure” if it is substantiallyfree of other components or other polypeptide components.

As used herein, “recombinant” refers to a biomolecule, e.g., a gene orpolypeptide, that (1) has been removed from its naturally occurringenvironment, (2) is not associated with all or a portion of apolynucleotide in which the gene is found in nature, (3) is operativelylinked to a polynucleotide which it is not linked to in nature, or (4)does not occur in nature. Also, “recombinant” refers to a cell or anorganism, such as a unicellular organism, herein termed a “recombinantunicellular organism,” a “recombinant host” or a “recombinant cell” thatcontains, produces and/or secretes a biomolecule, which can be arecombinant biomolecule or a non-recombinant biomolecule. For example, arecombinant unicellular organism may contain a recombinant nucleic acidproviding for enhanced production and/or secretion of a recombinantpolypeptide or a non-recombinant polypeptide. A recombinant cell ororganism, is also intended to refer to a cell into which a recombinantnucleic acid such as a recombinant vector has been introduced. A“recombinant unicellular organism” includes a recombinant microorganismhost cell and refers not only to the particular subject cell but to theprogeny of such a cell. Because certain modifications may occur insucceeding generations due to either mutation or environmentalinfluences, such progeny may not, in fact, be identical to the parentcell, but are still included within the scope of the terms herein. Theterm “recombinant” can be used in reference to cloned DNA isolates,chemically-synthesized polynucleotide analogs, or polynucleotide analogsthat are biologically synthesized by heterologous systems, as well aspolypeptides and/or mRNAs encoded by such nucleic acids. Thus, forexample, a polypeptide synthesized by a microorganism is recombinant,for example, if it is produced from an mRNA transcribed from arecombinant gene or other nucleic acid sequence present in the cell.

As used herein, an endogenous nucleic acid sequence in the genome of anorganism (or the encoded polypeptide product of that sequence) is deemed“recombinant” herein if a heterologous sequence is placed adjacent tothe endogenous nucleic acid sequence, such that the expression of thisendogenous nucleic acid sequence is altered. In this context, aheterologous sequence is a sequence that is not naturally adjacent tothe endogenous nucleic acid sequence, whether or not the heterologoussequence is itself endogenous (originating from the same host cell orprogeny thereof) or exogenous (originating from a different host cell orprogeny thereof). By way of example, a promoter sequence can besubstituted (e.g., by homologous recombination) for the native promoterof a gene in the genome of a host cell, such that this gene has analtered expression pattern. This gene would now become “recombinant”because it is separated from at least some of the sequences thatnaturally flank it. A nucleic acid is also considered “recombinant” ifit contains any modifications that do not naturally occur to thecorresponding nucleic acid in a genome. For instance, an endogenouscoding sequence is considered “recombinant” if it contains an insertion,deletion or a point mutation introduced artificially, e.g., by humanintervention. A “recombinant nucleic acid” also includes a nucleic acidintegrated into a host cell chromosome at a heterologous site and anucleic acid construct present as an episome.

The term “recombinant host cell” (or simply “recombinant cell” or “hostcell”), as used herein, is intended to refer to a cell into which arecombinant nucleic acid such as a recombinant vector has beenintroduced. In some instances the word “cell” is replaced by a namespecifying a type of cell. For example, a “recombinant microorganism” isa recombinant host cell that is a microorganism host cell and a“recombinant cyanobacteria” is a recombinant host cell that is acyanobacteria host cell. It should be understood that such terms areintended to refer not only to the particular subject cell but to theprogeny of such a cell. Because certain modifications may occur insucceeding generations due to either mutation or environmentalinfluences, such progeny may not, in fact, be identical to the parentcell, but are still included within the scope of the term “recombinanthost cell,” “recombinant cell,” and “host cell”, as used herein. Arecombinant host cell can be an isolated cell or cell line grown inculture or can be a cell which resides in a living tissue or organism.

As used herein, “sarcopenia” refers to the degenerative loss of skeletalmuscle mass (typically 0.5-1% loss per year after the age of 25),quality, and strength associated with aging. Sarcopenia is a componentof the frailty syndrome. The European Working Group on Sarcopenia inOlder People (EWGSOP) has developed a practical clinical definition andconsensus diagnostic criteria for age-related sarcopenia. For thediagnosis of sarcopenia, the working group has proposed using thepresence of both low muscle mass and low muscle function (strength orperformance). Sarcopenia is characterized first by a muscle atrophy (adecrease in the size of the muscle), along with a reduction in muscletissue “quality,” caused by such factors as replacement of muscle fibreswith fat, an increase in fibrosis, changes in muscle metabolism,oxidative stress, and degeneration of the neuromuscular junction.Combined, these changes lead to progressive loss of muscle function andeventually to frailty. Frailty is a common geriatric syndrome thatembodies an elevated risk of catastrophic declines in health andfunction among older adults. Contributors to frailty can includesarcopenia, osteoporosis, and muscle weakness. Muscle weakness, alsoknown as muscle fatigue, (or “lack of strength”) refers to the inabilityto exert force with one's skeletal muscles. Weakness often followsmuscle atrophy and a decrease in activity, such as after a long bout ofbedrest as a result of an illness. There is also a gradual onset ofmuscle weakness as a result of sarcopenia. Thus, sarcopenia is anexemplary condition associated with muscle wasting.

As used herein, “satiation” is the act of becoming full while eating ora reduced desire to eat. This halts or diminishes eating.

As used herein, “satiety” is the act of remaining full after a mealwhich manifests as the period of no eating follow the meal.

As used herein, “secrete.” “secretion” and “secreted” all refer to theact or process by which a polypeptide is relocated from the cytoplasm ofa cell of a multicellular organism or unicellular organism into theextracellular milieu thereof. As provided herein, such secretion mayoccur actively or passively. Further, the terms “excrete,” “excretion”and “excreted” generally connote passive clearing of a material from acell or unicellular organism: however, as appropriate such terms can beassociated with the production and transfer of materials outwards fromthe cell or unicellular organism.

In general, “stringent hybridization” is performed at about 25° C. belowthe thermal melting point (Tm) for the specific DNA hybrid under aparticular set of conditions. “Stringent washing” is performed attemperatures about 5° C. lower than the Tm for the specific DNA hybridunder a particular set of conditions. The Tm is the temperature at which50% of the target sequence hybridizes to a perfectly matched probe. SeeSambrook et al., Molecular Cloning: A Laboratory Manual, 2d ed., ColdSpring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989), page9.51, hereby incorporated by reference. For purposes herein, “stringentconditions” are defined for solution phase hybridization as aqueoushybridization (i.e., free of formamide) in 6×SSC (where 20×SSC contains3.0 M NaCl and 0.3 M sodium citrate), 1% SDS at 65° C. for 8-12 hours,followed by two washes in 0.2×SSC, 0.1% SDS at 65° C. for 20 minutes. Itwill be appreciated by the skilled worker that hybridization at 65° C.will occur at different rates depending on a number of factors includingthe length and percent identity of the sequences which are hybridizing.

The term “substantial homology” or “substantial similarity,” whenreferring to a nucleic acid or fragment thereof, indicates that, whenoptimally aligned with appropriate nucleotide insertions or deletionswith another nucleic acid (or its complementary strand), there isnucleotide sequence identity in at least about 76%, 80%, 85%, or atleast about 90%, or at least about 95%, 96%, 97%, 98% or 99% of thenucleotide bases, as measured by any well-known algorithm of sequenceidentity, such as FASTA, BLAST or Gap, as discussed above.

The term “sufficient amount” means an amount sufficient to produce adesired effect. e.g., an amount sufficient to modulate proteinaggregation in a cell.

A “synthetic” RNA, DNA or a mixed polymer is one created outside of acell, for example one synthesized chemically.

The term “therapeutically effective amount” is an amount that iseffective to ameliorate a symptom of a disease. A therapeuticallyeffective amount can be a “prophylactically effective amount” asprophylaxis can be considered therapy.

As used herein, “thermogenesis” is the process of heat production in amammal. Thermogenesis is accompanied by an increase in energyexpenditure. Thermogenesis is specifically the energy burned followingthe metabolism of a food component (such as protein). This may also bereferred to as the thermic effect of food. Total energy expenditure byan individual equals the sum of resting energy expenditure (energyconsumed at rest in a fasting state to support basal metabolism), thethermic effect of food, and energy expenditure related to physicalactivity. Resting energy expenditure accounts for about 65-75% of totalenergy expenditure in humans. The amount and activity of muscle mass isone influencer of resting energy expenditure. Adequate proteinconsumption to support muscle also influences resting energyexpenditure. The ingestion of protein tends to increase energyexpenditure following a meal; this is the thermic effect of food. Thethermic effect of food accounts for about 10% of total energyexpenditure in humans. While this is a small proportion of total energyexpenditure, small increases in this value can impact body weight.Protein has a higher thermic effect than fat or carbohydrate; thiseffect along with other metabolic influences of protein makes it auseful substrate for weight control, diabetes management and otherconditions.

As used herein, a “vector” is intended to refer to a nucleic acidmolecule capable of transporting another nucleic acid to which it hasbeen linked. One type of vector is a “plasmid,” which generally refersto a circular double stranded DNA loop into which additional DNAsegments can be ligated, but also includes linear double-strandedmolecules such as those resulting from amplification by the polymerasechain reaction (PCR) or from treatment of a circular plasmid with arestriction enzyme. Other vectors include cosmids, bacterial artificialchromosomes (BAC) and yeast artificial chromosomes (YAC). Another typeof vector is a viral vector, wherein additional DNA segments can beligated into the viral genome (discussed in more detail below). Certainvectors are capable of autonomous replication in a host cell into whichthey are introduced (e.g., vectors having an origin of replication whichfunctions in the host cell). Other vectors can be integrated into thegenome of a host cell upon introduction into the host cell, and arethereby replicated along with the host genome. Moreover, certain vectorsare capable of directing the expression of genes to which they areoperatively linked. Such vectors are referred to herein as “recombinantexpression vectors” (or simply “expression vectors”).

Nutritive Polypeptides and Amino Acid Sequences

Proteins present in dietary food sources can vary greatly in theirnutritive value. Provided are nutritive polypeptides that have enhancednutritive value and physiological and pharmacological effects due totheir amino acid content and digestibility. Provided are nutritivepolypeptides that have enhanced levels of essential amino acids, theinadequate availability of such essential amino acids in a personnegatively impacts general health and physiology through theperturbation of a network of cellular functions, and is associated witha wide array of health issues and diseases. Also provided are nutritivepolypeptides that have reduced levels of certain amino acids, thepresence or overabundance of such amino acids in the diet of an affectedsubject results in increased morbidity and mortality.

Traditionally, nutritionists and health researchers have utilizedspecific source ingredients (e.g., whey protein, egg whites, soya) orfractionates and isolates (e.g., soy protein isolates) to modulate therelative concentration of total protein in the diet, without the abilityto modulate the specific amino acid constituents.

Herein provided are nutritive polypeptides capable of transforminghealth and treating, preventing and reducing the severity of a multitudeof diseases, disorders and conditions associated with amino acidpathophysiology, as they are selected for specific physiologic benefitsto improve health and address many nutrition-related conditions,including gastrointestinal malabsorption, muscle wasting, diabetes orpre-diabetes, obesity, oncology, metabolic diseases, and other cellularand systemic diseases. Also provided are the compositions andformulations that contain the nutritive polypeptides, as food,beverages, medical foods, supplements, and pharmaceuticals.

Herein are provided important elucidations in the genomics, proteomics,protein characterization and production of nutritive polypeptides. Thepresent invention utilizes the synergistic advancements, describedherein, of (a) the genomics of edible species-those human food sourceorganisms, and human genomics, (b) substantial advances in proteinidentification and quantification in food protein and food nucleic acidlibraries, (c) new correlations between protein physical chemistry,solubility, structure-digestibility relationships and amino acidabsorption and metabolism in animals and humans. (d) physiology andpathophysiology information of how amino acids, the components ofnutritive polypeptides, affect protein malnutrition, chronic disease,responses to acute injury, and aging. (e) recombinant nutritivepolypeptide production utilizing a phylogenetically broad spectrum ofhost organisms, (f) qualification of allergenicity and toxicogenicityand in vitro and in vivo tests to assess human safety of orally consumednutritive polypeptides.

Identification and Selection of Amino Acid Sequences Encoding NutritivePolypeptides.

In its broadest sense, a nutritive polypeptide encompasses a polypeptidecapable of delivering amino acid and peptide nutrition to its intendedconsumer, who derives a benefit from such consumption. Each nutritivepolypeptide contains one or more amino acid sequences, and the presentinvention provides methods by which an amino acid sequence is identifiedand utilized in production, formulation and administration of thenutritive polypeptide having such an amino acid sequence.

In some embodiments, the source of a nutritive polypeptide amino acidsequence encompasses any protein-containing material, e.g., a food,beverage, composition or other product, known to be eaten, or otherwiseconsidered suitable for consumption, without deleterious effect by,e.g., a human or other organism, in particular a mammal.

Nutritive Polypeptide Amino Acid Sequences Derived from Edible Species.

In some embodiments a nutritive polypeptide comprises or consists of aprotein or fragment of a protein that naturally occurs in an edibleproduct, such as a food, or in the organism that generates biologicalmaterial used in or as the food. In some embodiments an “edible species”is a species known to produce a protein that can be eaten by humanswithout deleterious effect. A protein or polypeptide present in anedible species, or encoded by a nucleic acid present in the ediblespecies, is termed an “edible species protein” or “edible speciespolypeptide” or, if the edible species is a species consumed by a human,the term “naturally occurring human food protein” is usedinterchangeably herein. Some edible products are an infrequent but knowncomponent of the diet of only a small group of a type of mammal in alimited geographic location while others are a dietary staple throughoutmuch of the world. In other embodiments an edible product is one notknown to be previously eaten by any mammal, but that is demonstrated tobe edible upon testing or analysis of the product or one or moreproteins contained in the product.

Food organisms include but are not limited to those organisms of ediblespecies disclosed in PCT/US2013/032232, filed Mar. 15, 2013,PCT/US2013/032180, filed Mar. 15, 2013, PCT/US2013/032225, filed Mar.15, 2013, PCT/US2013/032218, filed Mar. 15, 2013, PCT/US2013/032212,filed Mar. 15, 2013, PCT/US2013/032206, filed Mar. 15, 2013, andPCT/US2013/038682, filed Apr. 29, 2013 and any phylogenetically relatedorganisms.

In some embodiments a nutritive polypeptide amino acid sequence isidentified in a protein that is present in a food source, such as anabundant protein in food, or is a derivative or mutein thereof, or is afragment of an amino acid sequence of a protein in food or a derivativeor mutein thereof. An abundant protein is a protein that is present in ahigher concentration in a food relative to other proteins present in thefood. Alternatively, a nutritive polypeptide amino acid sequence isidentified from an edible species that produces a protein containing theamino acid sequence in relatively lower abundance, but the protein isdetectable in a food product derived from the edible species, or frombiological material produced by the edible species. In some embodimentsa nucleic acid that encodes the protein is detectable in a food productderived from the edible species, or the nucleic acid is detectable froma biological material produced by the edible species. An edible speciescan produce a food that is a known component of the diet of only a smallgroup of a type of mammal in a limited geographic location, or a dietarystaple throughout much of the world.

Exemplary edible species include animals such as goats, cows, chickens,pigs and fish. In some embodiments the abundant protein in food isselected from chicken egg proteins such as ovalbumin. ovotransferrin,and ovomucuoid; meat proteins such as myosin, actin, tropomyosin,collagen, and troponin; cereal proteins such as casein, alpha1 casein,alpha2 casein, beta casein, kappa casein, beta-lactoglobulin,alpha-lactalbumin. glycinin, beta-conglycinin, glutelin, prolamine,gliadin, glutenin, albumin, globulin; chicken muscle proteins such asalbumin, enolase, creatine kinase, phosphoglycerate mutase,triosephosphate isomerase, apolipoprotein, ovotransferrin,phosphoglucomutase, phosphoglycerate kinase, glycerol-3-phosphatedehydrogenase, glyceraldehyde 3-phosphate dehydrogenase, hemoglobin,cofilin, glycogen phosphorylase, fructose-1,6-bisphosphatase, actin,myosin, tropomyosin a-chain, casein kinase, glycogen phosphorylase,fructose-1,6-bisphosphatase, aldolase, tubulin, vimentin, endoplasmin,lactate dehydrogenase, destrin, transthyretin, fructose bisphosphatealdolase, carbonic anhydrase, aldehyde dehydrogenase, annexin, adenosylhomocysteinase; pork muscle proteins such as actin, myosin, enolase,titin, cotilin, phosphoglycerate kinase, enolase, pyruvatedehydrogenase, glycogen phosphorylase, triosephosphate isomerase,myokinase; and fish proteins such as parvalbumin, pyruvatedehydrogenase, desmin, and triosephosphate isomerase.

Nutritive polypeptides may contain amino acid sequences present inedible species polypeptides. In one embodiment, a biological materialfrom an edible species is analyzed to determine the protein content inthe biological material. An exemplary method of analysis is to use massspectrometry analysis of the biological material, as provided in theExamples below. Another exemplary method of analysis is to generate acDNA library of the biological material to create a library of ediblespecies cDNAs, and then express the cDNA library in an appropriaterecombinant expression host, as provided in the Examples below. Anotherexemplary method of analysis is query a nucleic acid and/or proteinsequence database as provided in the Examples below.

Determination of amino acid ratios and amino acid density in a nutritivepolypeptide. In some instances herein the portion of amino acid(s) of aparticular type within a polypeptide, protein or a composition isquantified based on the weight ratio of the type of amino acid(s) to thetotal weight of amino acids present in the polypeptide, protein orcomposition in question. This value is calculated by dividing the weightof the particular amino acid(s) in the polypeptide, protein or acomposition by the weight of all amino acids present in the polypeptide,protein or a composition.

In other instances the ratio of a particular type of amino acid(s)residues present in a polypeptide or protein to the total number ofamino acids present in the polypeptide or protein in question is used.This value is calculated by dividing the number of the amino acid(s) inquestion that is present in each molecule of the polypeptide or proteinby the total number of amino acid residues present in each molecule ofthe polypeptide or protein. A skilled artisan appreciates that these twomethods are interchangeable and that the weight proportion of a type ofamino acid(s) present in a polypeptide or protein can be converted to aratio of the particular type of amino acid residue(s), and vice versa.

In some aspects the nutritive polypeptide is selected to have a desireddensity of one or more essential amino acids (EAA). Essential amino aciddeficiency can be treated or prevented with the effective administrationof the one or more essential amino acids otherwise absent or present ininsufficient amounts in a subject's diet. For example, EAA density isabout equal to or greater than the density of essential amino acidspresent in a full-length reference nutritional polypeptide, such asbovine lactoglobulin, bovine beta-casein or bovine type I collagen,e.g., EAA density in a nutritive polypeptide is at least about 5%, 10%,15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 90%, 95%, 100%, 200%, 300%, 400%, 500% or above 500% greater than areference nutritional polypeptide or the polypeptide present in anagriculturally-derived food product.

In some aspects the nutritive polypeptide is selected to have a desireddensity of aromatic amino acids (“AAA”, including phenylalanine,tryptophan, tyrosine, histidine, and thyroxine). AAAs are useful, e.g.,in neurological development and prevention of exercise-induced fatigue.For example, AAA density is about equal to or greater than the densityof essential amino acids present in a full-length reference nutritionalpolypeptide, such as bovine lactoglobulin, bovine beta-casein or bovinetype I collagen, e.g., AAA density in a nutritive polypeptide is atleast about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200%, 300%, 400%, 500% or above500% greater than a reference nutritional polypeptide or the polypeptidepresent in an agriculturally-derived food product.

In some aspects the nutritive polypeptide is selected to have a desireddensity of branched chain amino acids (BCAA). For example, BCAA density,either individual BCAAs or total BCAA content is about equal to orgreater than the density of branched chain amino acids present in afull-length reference nutritional polypeptide, such as bovinelactoglobulin, bovine beta-casein or bovine type I collagen, e.g., BCAAdensity in a nutritive polypeptide is at least about 5%, 10%, 15%, 20%,25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 100%, 200%, 300%, 400%, 500% or above 500% greater than a referencenutritional polypeptide or the polypeptide present in anagriculturally-derived food product. BCAA density in a nutritivepolypeptide can also be selected for in combination with one or moreattributes such as EAA density.

In some aspects the nutritive polypeptide is selected to have a desireddensity of amino acids arginine, glutamine and/or leucine (RQL aminoacids). For example, RQL amino acid density is about equal to or greaterthan the density of essential amino acids present in a full-lengthreference nutritional polypeptide, such as bovine lactoglobulin, bovinebeta-casein or bovine type I collagen, e.g., RQL amino acid density in anutritive polypeptide is at least about 5%, 10%, 15%, 20%, 25%, 30%,35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%,200%, 300%, 400%, 500% or above 500% greater than a referencenutritional polypeptide or the polypeptide present in anagriculturally-derived food product.

In some aspects the nutritive polypeptide is selected to have a desireddensity or distribution of post-translational modifications (PTMs). Forexample, PTMs include addition, removal or redistribution ofbiotinylation, pegylation, acylation, alkylation, butyrylationglycosylation, hydroxylation, iodination, oxidation, propionylation,malonylation, myristoylation, palmitoylation, isoprenylation,succinylation, selenoylation, SUMOylation, ubiquitination, andglypiation removal or redistribution of disulfide bridges.

In certain embodiments herein the weight proportion of branched chainamino acids, leucine, and/or essential amino acids in whey, egg, or soyis used as a benchmark to measure the amino acid composition of apolypeptide, a protein, or a composition comprising at least one of apolypeptide and a protein. In those embodiments it is understood thatthe two measures are not completely equivalent, but it is alsounderstood that the measures result in measurements that are similarenough to use for this purpose. For example, when a protein of interestis characterized as comprising a ratio of branched chain amino acidresidues to total amino acid residues that is equal to or greater than24% (the weight proportion of branched chain amino acid residues presentin whey), that is a precise description of the branched chain amino acidcontent of the protein. At the same time, the weight proportion ofbranched chain amino acid residues present in that protein is notnecessarily exactly equal to 24%. Even so, the skilled artisanunderstands that this is a useful comparison. If provided with the totalnumber of amino acid residues present in the protein of interest theskilled artisan can also determine the weight proportion of branchedchain amino acid residues in the protein of interest.

In some embodiments a protein according to this disclosure comprises afirst polypeptide sequence comprising a fragment of an edible speciespolypeptide. In some embodiments of the nutritive protein, the proteinconsists of the first polypeptide sequence. In some embodiments of thenutritive protein, the protein consists of the fragment of an ediblespecies polypeptide.

In some embodiments a protein according to this disclosure comprises afirst polypeptide sequence that comprises ratio of branched chain aminoacid residues to total amino acid residues that is equal to or greaterthan the ratio of branched chain amino acid residues to total amino acidresidues present in at least one of whey protein, egg protein, and soyprotein. Thus, in such embodiments the protein comprises a firstpolypeptide sequence that comprises a ratio of branched chain amino acidresidues to total amino acid residues that is equal to or greater than aratio selected from 24%, 20%, and 18%. In other embodiments, the proteincomprises a first polypeptide sequence that comprises a ratio ofbranched chain amino acid residues to total amino acid residues that isequal to or greater than a percentage ratio selected from 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 75, 80, 85, 90, 95, or 100%.

In some embodiments a protein according to this disclosure comprises afirst polypeptide sequence that comprises a ratio of L (leucine)residues to total amino acid residues that is equal to or greater thanthe ratio of L residues to total amino acid residues present in at leastone of whey protein, egg protein, and soy protein. In other embodiments,the protein comprises a first polypeptide sequence that comprises aratio of leucine residues to total amino acid residues that is equal toor greater than a percentage ratio selected from 1, 2, 3, 4, 5, 6, 7, 8,9, 11, II, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, or greater than 30%.

In some embodiments a protein according to this disclosure comprises afirst polypeptide sequence that comprises a ratio of essential aminoacid residues to total amino acid residues that is equal to or greaterthan the ratio of essential amino acid residues to total amino acidresidues present in at least one of whey protein, egg protein, and soyprotein. In other embodiments, the protein comprises a first polypeptidesequence that comprises a ratio of essential chain amino acid residuesto total amino acid residues that is equal to or greater than apercentage ratio selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66,67, 68, 69, 70, 75, 80, 85, 90, 95, or 100%.

In some embodiments the protein comprises a first polypeptide sequencethat comprises a ratio of branched chain amino acid residues to totalamino acid residues that is equal to or greater than the ratio ofbranched chain amino acid residues to total amino acid residues presentin at least one of whey protein, egg protein, and soy protein; and/orcomprises a first polypeptide sequence that comprises a ratio of L(leucine) residues to total amino acid residues that is equal to orgreater than the ratio of L residues to total amino acid residuespresent in at least one of whey protein, egg protein, and soy protein,and/or comprises a first polypeptide sequence that comprises a ratio ofessential amino acid residues to total amino acid residues that is equalto or greater than the ratio of essential amino acid residues to totalamino acid residues present in at least one of whey protein, eggprotein, and soy protein.

In some embodiments the protein comprises a first polypeptide sequencethat comprises a ratio of branched chain amino acid residues to totalamino acid residues that is equal to or greater than the ratio ofbranched chain amino acid residues to total amino acid residues presentin at least one of whey protein, egg protein, and soy protein; andcomprises a first polypeptide sequence that comprises a ratio ofessential amino acid residues to total amino acid residues that is equalto or greater than the ratio of essential amino acid residues to totalamino acid residues present in at least one of whey protein, eggprotein, and soy protein. In some embodiments the protein comprises afirst polypeptide sequence that comprises a ratio of branched chainamino acid residues to total amino acid residues equal to or greaterthan 24% and a ratio of essential amino acid residues to total aminoacid residues that is equal to or greater than 49%. In some embodimentsthe protein comprises a first polypeptide sequence that comprises aratio of branched chain amino acid residues to total amino acid residuesequal to or greater than 20% and a ratio of essential amino acidresidues to total amino acid residues that is equal to or greater than51%. In some embodiments the protein comprises a first polypeptidesequence that comprises a ratio of branched chain amino acid residues tototal amino acid residues equal to or greater than 18% and a ratio ofessential amino acid residues to total amino acid residues that is equalto or greater than 40%.

In some embodiments the protein comprises a first polypeptide sequencethat comprises a ratio of L (leucine) residues to total amino acidresidues that is equal to or greater than the ratio of L residues tototal amino acid residues present in at least one of whey protein, eggprotein, and soy protein; and comprises a first polypeptide sequencethat comprises a ratio of essential amino acid residues to total aminoacid residues that is equal to or greater than the ratio of essentialamino acid residues to total amino acid residues present in at least oneof whey protein, egg protein, and soy protein. In some embodiments theprotein comprises a first polypeptide sequence that comprises a ratio ofL (leucine) residues to total amino acid residues equal to or greaterthan 11% and a ratio of essential amino acid residues to total aminoacid residues that is equal to or greater than 49%. In some embodimentsthe protein comprises a first polypeptide sequence that comprises aratio of L (leucine) amino acid residues to total amino acid residuesequal to or greater than 9% and a ratio of essential amino acid residuesto total amino acid residues that is equal to or greater than 51%. Insome embodiments the protein comprises a first polypeptide sequence thatcomprises a ratio of L (leucine) amino acid residues to total amino acidresidues equal to or greater than 8% and a ratio of essential amino acidresidues to total amino acid residues that is equal to or greater than40%. In some embodiments of the protein, the first polypeptide sequencecomprises a first polypeptide sequence comprising a ratio of branchedchain amino acid residues to total amino acid residues equal to orgreater than 24%, a ratio of L (leucine) residues to total amino acidresidues that is equal to or greater than 11%, and comprises at leastone of every essential amino acid. In some embodiments of the protein,the first polypeptide sequence comprises a first polypeptide sequencecomprising a ratio of branched chain amino acid residues to total aminoacid residues equal to or greater than 24% and a ratio of essentialamino acid residues to total amino acid residues equal to or greaterthan 49%.

Provided are nutritive polypeptides that are nutritionally complete. Insome embodiments of the protein, the first polypeptide sequencecomprises a first polypeptide sequence that contains at least one ofevery essential amino acid.

Nutritive Glycoproteins and Nutritive Polypeptides with ModulatedGlycosylation.

The term “glycan” or “glycoyl” refers to a polysaccharide oroligosaccharide which may be linked to a polypeptide, lipid, orproteoglycan. In some embodiments, a glycan is linked covalently ornon-covalently to the polypeptide. In some embodiments the linkageoccurs via a glycosidic bond. In some embodiments, the linkage isdirectly between the glycan (or glycoyl) and polypeptide or via anintermediary molecule. In some embodiments, the glycosidic bond isN-linked or O-linked. The term “polysaccharide” or “oligosaccharide”refers to one or more monosaccharide units joined together by glycosidicbonds. In some embodiments, the polysaccharide or oligosaccharide has alinear or branched structure. In some embodiments, the monosaccharideunits comprise N-acetyl galactosamine, N-acetylglucosamine, galactose,neuraminic acid, fructose, mannose, fucose, glucose, xylose,N-acetylneuraminic acid, N-glycolylneuraminic acid,O-lactyl-N-acetylneuraminic acid, O-acetyl-N-acetylneuraminic acid, orO-methyl-N-acetylneuraminic acid. In some embodiments, themonosaccharide is modified by a phosphate, sulfate, or acetate group.The term “glycosylation acceptor site” refers to an amino acid along apolypeptide which carries a glycan or glycoyl in the native composition.In some embodiments the acceptor site consists of a nucleophilicacceptor of a glycosidic bond. In some embodiments, the nucleophilicacceptor site consists of an amino group. In some embodiments the aminoacid consists of an asparagine, arginine, serine, threonine,hydroxyproline, hydroxylysine, tryptophan, phosphothreonine, serine, orphosphoserine. The term “exogenous glycosylation acceptor site” refersto a glycosylation acceptor site not present in the native compositionof the polypeptide. In some embodiments the amino acid for the exogenousglycosylation acceptor site did not carry a glycan or glycoyl in thenative composition. In some embodiments, the amino acid does not occurin the primary sequence of the polypeptide in the native composition.The term “exogenous glycan” or “exogenous glycoyl” refers to a glycan orglycoyl that occupies a glycosylation acceptor site, which was notpresent in the native composition on the same glycosylation acceptorsite. In some embodiments, the glycosylation acceptor site is anexogenous glycosylation site or a native glycosylation site. The term“glycoprotein” refers to a polypeptide that is bound to at least oneglycan or glycoyl.

Disclosed herein are formulations containing isolated nutritivepolypeptides at least one exogenous glycosylation acceptor site presenton an amino acid of the nutritive polypeptide. In some aspects, the atleast one exogenous glycosylation acceptor site is occupied by anexogenous glycoyl or glycan, or alternatively, is unoccupied or isoccupied by a non-natively occupying glycol or glycan. In someembodiments, the nutritive polypeptide is a polypeptide having an aminoacid sequence at least 90% identical to SEQID 00001-03909 and SEQID04129-44483, or is an edible species polypeptide sequence or fragmentthereof at least 50 amino acids in length, or is a polypeptide havingsubstantial immunogenicity when the glycosylation acceptor site is notpresent or is unoccupied. The nutritive polypeptide is morethermostable, is more digestible, and/or has a lower aggregation scorethan a reference polypeptide that has an amino acid sequence identicalto the nutritive polypeptide but the glycosylation acceptor site is notpresent or is unoccupied in the reference polypeptide. The amino acids,e.g., asparagine, arginine, serine, threonine, hydroxyproline, andhydroxylysine, containing an exogenous glycosylation acceptor site areresistant to proteolysis. Exemplary glycans are N-acetyl galactosamine,N-acetylglucosamine, galactose, neuraminic acid, fructose, mannose,fucose, glucose, xylose, N-acetylneuraminic acid, N-glycolylneuraminicacid, O-lactyl-N-acetylneuraminic acid. O-acetyl-N-acetylneuraminicacid, and O-methyl-N-acetylneuraminic acid.

In some embodiments provided are formulations containing a nutritivepolypeptide that is identical to the amino acid sequence of apolypeptide in a reference edible species glycoprotein, but thecarbohydrate component of the nutritive polypeptide differs from acarbohydrate component of the reference edible species glycoprotein. Thenutritive polypeptide is produced, for example, by expressing thepolypeptide of the reference glycoprotein in a non-native host such asAspergillus, Bacillus. Saccharomyces or a mammalian cell. Also providedare variant nutritive polypeptides, where the amino acid sequencediffers from the amino acid sequence of a polypeptide in a referenceglycoprotein by <1%, <5%, <10%, or more than 10%, and the mass of thecarbohydrate component of the nutritive polypeptide is different fromthe mass of the carbohydrate component of the reference glycoprotein.The nutritive polypeptide variant is created by the insertion, deletion,substitution, or replacement of amino acid residues in the amino acidsequence of the polypeptide of the reference glycoprotein. Preferably,the nutritive polypeptide has distinguishable chemical biochemical,biophysical, biological, or immunological properties from the referenceglycoprotein. For example, the nutritive polypeptide is morehygroscopic, hydrophilic, or soluble in aqueous solutions than thereference glycoprotein. Alternatively, the nutritive polypeptide is lesshygroscopic, hydrophilic, or soluble in aqueous solutions than thereference glycoprotein.

In another example, the nutritive polypeptide is more antigenic,immunogenic, or allergenic than the reference glycoprotein, oralternatively, the nutritive polypeptide is less antigenic, immunogenic,or allergenic than the reference glycoprotein. The nutritive polypeptideis more stable or resistant to enzymatic degradation than the referenceglycoprotein or the nutritive polypeptide is more unstable orsusceptible to enzymatic degradation than the reference glycoprotein.The carbohydrate component of the nutritive polypeptide is substantiallyfree of N-glycolylneuraminic acid or has reduced N-glycolylneuraminicacid in comparison to the reference glycoprotein. Alternatively, thecarbohydrate component of the nutritive polypeptide has elevatedN-glycolylneuraminic acid in comparison to the reference glycoprotein.

Also provided is a nutritive polypeptide that has at least one exogenousglycosylation acceptor site present on an amino acid of the nutritivepolypeptide, and the at least one exogenous glycosylation acceptor siteis occupied by an exogenous glycoyl or glycan, and the nutritivepolypeptide includes a polypeptide having an amino acid sequence atleast 90% identical to SEQID 00001-03909 and SEQID 04129-44483, wherethe nutritive polypeptide is present in at least 0.5 g at aconcentration of at least 10% on a mass basis, and where the formulationis substantially free of non-comestible products

Reference Nutritional Polypeptides and Reference Nutritional PolypeptideMixtures.

Three natural sources of protein generally regarded as good sources ofhigh quality amino acids are whey protein, egg protein, and soy protein.Each source comprises multiple proteins. Table RNP1 presents the weightproportional representation of each amino acid in the protein source (gAA/g protein) expressed as a percentage.

TABLE RNP1 Amino Acid Whey Egg Soy Isoleucine  6.5%  5.5%  5.0% Leucine11.0%  8.6%  8.0% Lysine  9.1%  7.2%  6.3% Methionine  2.1%  3.1%  1.3%Phenylalanine  3.4%  5.3%  1.2% Threonine  7.0%  4.8%  3.7% Tryptophan 1.7%  1.2%  1.3% Valine  6.2%  6.1%  4.9% Histidine  2.0%  2.4%  2.7%Other 51.7% 49.5% 60.4%

Table RNP2 presents the weight proportion of each protein source that isessential amino acids, branched chain amino acids (L. I, and V), andleucine (L) (alone).

TABLE RNP2 Essential Amino Branched Chain Protein Source Acids AminoAcids Leucine Whey 49.0% 23.7% 11.0% Egg 50.5% 20.1%  8.6% Soy 39.6%17.9%  8.0%

The sources relied on to determine the amino acid content of Whey are:Belitz H D., Grosch W., and Schieberle P. Food Chemistry (4th Ed).Springer-Verlag, Berlin Heidelberg 2009:gnc.com/product/index.jsp?productId=2986027;nutrabio.com/Products/whey_protein_concentrate.htm; andnutrabio.com/Products/whey_protein_isolate.htm. The amino acid contentvalues from those sources were averaged to give the numbers presented inTables RNP1 and RNP2. The source for soy protein is Egg. NationalNutrient Database for Standard Reference, Release 24(ndb.nal.usda.gov/ndb/foods/list). The source for soy protein is SelfNutrition Data(nutritiondata.self.com/factsilegumes-and-legume-products/4389/2).

According to the USDA nutritional database whey can include variousnon-protein components: water, lipids (such as fatty acids andcholesterol), carbohydrates and sugars, minerals (such as Ca, Fe, Mg, P,K, Na, and Zn), and vitamins (such as vitamin C, thiamin, riboflavin,niacin, vitamin B-6, folate, vitamin B-12, and vitamin A). According tothe USDA nutritional database egg white can include various non-proteincomponents: water, lipids, carbohydrates, minerals (such as Ca, Fe, Mg,P, K, Na, and Zn), and vitamins (such as thiamin, riboflavin, niacin,vitamin B-6, folate, and vitamin B-12). According to the USDAnutritional database soy can include various non-protein components:water, lipids (such as fatty acids), carbohydrates, minerals (such asCa, Fe, Mg, P, K, Na, and Zn), and vitamins (such as thiamin,riboflavin, niacin, vitamin B-6, folate).

Engineered Nutritive Polypeptides

In some embodiments a protein comprises or consists of a derivative ormutein of a protein or fragment of an edible species protein or aprotein that naturally occurs in a food product. Such a protein can bereferred to as an “engineered protein.” In such embodiments the naturalprotein or fragment thereof is a “reference” protein or polypeptide andthe engineered protein or a first polypeptide sequence thereof comprisesat least one sequence modification relative to the amino acid sequenceof the reference protein or polypeptide. For example, in someembodiments the engineered protein or first polypeptide sequence thereofis at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5%identical to at least one reference protein amino acid sequence.Typically the ratio of at least one of branched chain amino acidresidues to total amino acid residues, essential amino acid residues tototal amino acid residues, and leucine residues to total amino acidresidues, present in the engineered protein or a first polypeptidesequence thereof is greater than the corresponding ratio of at least oneof branched chain amino acid residues to total amino acid residues,essential amino acid residues to total amino acid residues, and leucineresidues to total amino acid residues present in the reference proteinor polypeptide sequence.

Nutritive Polypeptides—Orthologs and Homologs.

In another aspect, provided are nutritive polypeptides that containamino acid sequences homologous to edible species polypeptides, whichare optionally secreted from unicellular organisms and purifiedtherefrom. Such homologous polypeptides can be 70%, 75%, 80%, 85%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater than 99% similar,or can be 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, 99% or greater than 99% identical to an edible species polypeptide.Such nutritive polypeptides can be endogenous to the host cell orexogenous, can be naturally secreted in the host cell, or both, and canbe engineered for secretion.

Also provided are orthologs of nutritive polypeptides. The disclosure ofa nutritive polypeptide sequence encompasses the disclosure of allorthologs of such a nutritive polypeptide sequence, fromphylogenetically related organisms or, alternatively, from aphylogenetically diverse organism that is homologous to the nutritivepolypeptide, such as 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greaterthan 99% similar, or can be 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99% or greater than 99% identical.

Nutritive Polypeptide Fragments. Nutritive Polypeptide Length.

In some embodiments herein a nutritive polypeptide contains a fragmentof an edible species polypeptide. In some embodiments the fragmentcomprises at least 25 amino acids. In some embodiments the fragmentcomprises at least 50 amino acids. In some embodiments the fragmentconsists of at least 25 amino acids. In some embodiments the fragmentconsists of at least 50 amino acids. In some embodiments an isolatedrecombinant protein is provided. In some embodiments the proteincomprises a first polypeptide sequence, and the first polypeptidesequence comprises a fragment of at least 25 or at least 50 amino acidsof an edible species protein. In some embodiments the proteins isisolated. In some embodiments the proteins are recombinant. In someembodiments the proteins comprise a first polypeptide sequencecomprising a fragment of at least 50 amino acids of an edible speciesprotein. In some embodiments the proteins are isolated recombinantproteins. In some embodiments the isolated recombinant proteinsdisclosed herein are provided in a non-isolated and/or non-recombinantform.

In some embodiments the protein comprises from 10 to 5,000 amino acids,from 20-2.000 amino acids, from 20-1,000 amino acids, from 20-500 aminoacids, from 20-250 amino acids, from 20-200 amino acids, from 20-150amino acids, from 20-100 amino acids, from 20-40 amino acids, from 30-50amino acids, from 40-60 amino acids, from 50-70 amino acids, from 60-80amino acids, from 70-90 amino acids, from 80-100 amino acids, at least10 amino acids, at least 11 amino acids, at least 12 amino acids, atleast 13 amino acids, at least 14 amino acids, at least 15 amino acids,at least 16 amino acids, at least 17 amino acids, at least 18 aminoacids, at least 19 amino acids, at least 20 amino acids, at least 21amino acids, at least 22 amino acids, at least 23 amino acids, at least24 amino acids, at least 25 amino acids, at least 30 amino acids, atleast 35 amino acids, at least 40 amino acids, at least 45 amino acids,at least 50 amino acids, at least 55 amino acids, at least 60 aminoacids, at least 65 amino acids, at least 70 amino acids, at least 75amino acids, at least 80 amino acids, at least 85 amino acids, at least90 amino acids, at least 95 amino acids, at least 100 amino acids, atleast 105 amino acids, at least 110 amino acids, at least 115 aminoacids, at least 120 amino acids, at least 125 amino acids, at least 130amino acids, at least 135 amino acids, at least 140 amino acids, atleast 145 amino acids, at least 150 amino acids, at least 155 aminoacids, at least 160 amino acids, at least 165 amino acids, at least 170amino acids, at least 175 amino acids, at least 180 amino acids, atleast 185 amino acids, at least 190 amino acids, at least 195 aminoacids, at least 200 amino acids, at least 205 amino acids, at least 210amino acids, at least 215 amino acids, at least 220 amino acids, atleast 225 amino acids, at least 230 amino acids, at least 235 aminoacids, at least 240 amino acids, at least 245 amino acids, or at least250 amino acids. In some embodiments the protein consists of from 20 to5,000 amino acids, from 20-2.000 amino acids, from 20-1,000 amino acids,from 20-500 amino acids, from 20-250 amino acids, from 20-200 aminoacids, from 20-150 amino acids, from 20-100 amino acids, from 20-40amino acids, from 30-50 amino acids, from 40-60 amino acids, from 50-70amino acids, from 60-80 amino acids, from 70-90 amino acids, from 80-100amino acids, at least 25 amino acids, at least 30 amino acids, at least35 amino acids, at least 40 amino acids, at least 2455 amino acids, atleast 50 amino acids, at least 55 amino acids, at least 60 amino acids,at least 65 amino acids, at least 70 amino acids, at least 75 aminoacids, at least 80 amino acids, at least 85 amino acids, at least 90amino acids, at least 95 amino acids, at least 100 amino acids, at least105 amino acids, at least 110 amino acids, at least 115 amino acids, atleast 120 amino acids, at least 125 amino acids, at least 130 aminoacids, at least 135 amino acids, at least 140 amino acids, at least 145amino acids, at least 150 amino acids, at least 155 amino acids, atleast 160 amino acids, at least 165 amino acids, at least 170 aminoacids, at least 175 amino acids, at least 180 amino acids, at least 185amino acids, at least 190 amino acids, at least 195 amino acids, atleast 200 amino acids, at least 205 amino acids, at least 210 aminoacids, at least 215 amino acids, at least 220 amino acids, at least 225amino acids, at least 230 amino acids, at least 235 amino acids, atleast 240 amino acids, at least 245 amino acids, or at least 250 aminoacids. In some aspects, a protein or fragment thereof includes at leasttwo domains: a first domain and a second domain. One of the two domainscan include a tag domain, which can be removed if desired. Each domaincan be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, or greater than 25 amino acids in length.For example, the first domain can be a polypeptide of interest that is18 amino acids in length and the second domain can be a tag domain thatis 7 amino acids in length. As another example, the first domain can bea polypeptide of interest that is 17 amino acids in length and thesecond domain can be a tag domain that is 8 amino acids in length.

In some embodiments herein a fragment of an edible species polypeptideis selected and optionally isolated. In some embodiments the fragmentcomprises at least 25 amino acids. In some embodiments the fragmentcomprises at least 50 amino acids. In some embodiments the fragmentconsists of at least 25 amino acids. In some embodiments the fragmentconsists of at least 50 amino acids. In some embodiments an isolatedrecombinant protein is provided. In some embodiments the proteincomprises a first polypeptide sequence, and the first polypeptidesequence comprises a fragment of at least 25 or at least 50 amino acidsof an edible species protein. In some embodiments the proteins isisolated. In some embodiments the proteins are recombinant. In someembodiments the proteins comprise a first polypeptide sequencecomprising a fragment of at least 50 amino acids of an edible speciesprotein. In some embodiments the proteins are isolated recombinantproteins. In some embodiments the isolated nutritive polypeptidesdisclosed herein are provided in a non-isolated and/or non-recombinantform.

Nutritive Polypeptide Physicochemical Properties.

Digestibility. In some aspects the nutritive polypeptide issubstantially digestible upon consumption by a mammalian subject.Preferably, the nutritive polypeptide is easier to digest than at leasta reference polypeptide or a reference mixture of polypeptides, or aportion of other polypeptides in the consuming subject's diet. As usedherein, “substantially digestible” can be demonstrated by measuringhalf-life of the nutritive polypeptide upon consumption. For example, anutritive polypeptide is easier to digest if it has a half-life in thegastrointestinal tract of a human subject of less than 60 minutes, orless than 50, 40, 30, 20, 15, 10, 5, 4, 3, 2 minutes or 1 minute. Incertain embodiments the nutritive polypeptide is provided in aformulation that provides enhanced digestion; for example, the nutritivepolypeptide is provided free from other polypeptides or other materials.In some embodiments, the nutritive polypeptide contains one or morerecognition sites for one or more endopeptidases. In a specificembodiment, the nutritive polypeptide contains a secretion leader (orsecretory leader) sequence, which is then cleaved from the nutritivepolypeptide. As provided herein, a nutritive polypeptide encompassespolypeptides with or without signal peptides and/or secretory leadersequences. In some embodiments, the nutritive polypeptide is susceptibleto cleavage by one or more exopeptidases.

Digestion Assays

Digestibility is a parameter relevant to the benefits and utility ofproteins. Information relating to the relative completeness of digestioncan serve as a predictor of peptide bioavailability (Daniel, H., 2003.Molecular and Integrative Physiology of Intestinal Peptide Transport.Annual Review of Physiology, Volume 66, pp. 361-384). In someembodiments proteins disclosed herein are screened to assess theirdigestibility. Digestibility of proteins can be assessed by any suitablemethod known in the art. In some embodiments digestibility is assessedby a physiologically relevant in vitro digestion reaction that includesone or both phases of protein digestion, simulated gastric digestion andsimulated intestinal digestion (see, e.g., Moreno, et al., 2005.Stability of the major allergen Brazil nut 2S albumin (Ber e1) tophysiologically relevant in vitro gastrointestinal digestion. FEBSJournal, pp. 341-352; Martos, G., Contreras. P., Molina, E. &Lopez-Fandino, R., 2010. Egg White Ovalbumin Digestion MimickingPhysiological Conditions. Journal of Agricultural and food chemistry,pp. 5640-5648; Moreno, F. J., Mackie, A. R. & Clare Mills, E. N., 2005).Phospholipid interactions protect the milk allergen a-Lactalbumin fromproteolysis during in vitro digestion. Journal of agricultural and foodchemistry, pp. 9810-9816). Briefly, test proteins are sequentiallyexposed to a simulated gastric fluid (SGF) for 120 minutes (the lengthof time it takes 90% of a liquid meal to pass from the stomach to thesmall intestine; see Kong., F. & Singh, R. P., 2008. Disintegration ofSolid Foods in Human Stomach. Journal of Food Science, pp. 67-80) andthen transferred to a simulated duodenal fluid (SDF) to digest for anadditional 120 minutes. Samples at different stages of the digestion(e.g., 2, 5, 15, 30, 60 and 120 min) are analyzed by electrophoresis(e.g., chip electrophoresis or SDS-PAGE) to monitor the size and amountof intact protein as well as any large digestion fragments (e.g., largerthan 4 kDa). The disappearance of protein over time indicates the rateat which the protein is digested in the assay. By monitoring the amountof intact protein observed over time, the half-life (τ½) of digestion iscalculated for SGF and, if intact protein is detected after treatmentwith SGF, the τ½ of digestion is calculated for SIF. This assay can beused to assess comparative digestibility (i.e., against a benchmarkprotein such as whey) or to assess absolute digestibility. In someembodiments the digestibility of the protein is higher (i.e., the SGF τ½and/or SIF τ½ is shorter) than whey protein. In some embodiments theprotein has a SGF τ½ of 30 minutes or less, 20 minutes or less, 15minutes or less, 10 minutes or less, 5 minutes or less, 4 minutes orless, 3 minutes or less, 2 minutes or less or 1 minute or less. In someembodiments the protein has a SIF τ½ of 30 minutes or less, 20 minutesor less, 15 minutes or less, 10 minutes or less, 5 minutes or less, 4minutes or less, 3 minutes or less, 2 minutes or less or 1 minute orless. In some embodiments the protein is not detectable in one or bothof the SGF and SIF assays by 2 minutes, 5 minutes, 15 minutes, 30minutes, 60 minutes, or 120 minutes. In some embodiments the protein isdigested at a constant rate and/or at a controlled rate in one or bothof SGF and SIF. In such embodiments the rate of digestion of the proteinmay not be optimized for the highest possible rate of digestion. In suchembodiments the rate of absorption of the protein following ingestion bya mammal can be slower and the total time period over which absorptionoccurs following ingestion can be longer than for proteins of similaramino acid composition that are digested at a faster initial rate in oneor both of SGF and SIF. In some embodiments the protein is completely orsubstantially completely digested in SGF. In some embodiments theprotein is substantially not digested or not digested by SGF; in mostsuch embodiments the protein is digested in SIF.

Assessing protein digestibility can also provide insight into aprotein's potential allergenicity, as proteins or large fragments ofproteins that are resistant to digestive proteases can have a higherrisk of causing an allergenic reaction (Goodman, R. E. et al., 2008.Allergenicity assessment of genetically modified crops—what makes sense?Nature Biotechnology, pp. 73-81). To detect and identify peptides toosmall for chip electrophoresis analysis, liquid chromatography and massspectrometry can be used. In SGF samples, peptides can be directlydetected and identified by LC/MS. SIF protein digestions may requirepurification to remove bile acids before detection and identification byLC/MS.

In some embodiments digestibility of a protein is assessed byidentification and quantification of digestive protease recognitionsites in the protein amino acid sequence. In some embodiments theprotein comprises at least one protease recognition site selected from apepsin recognition site, a trypsin recognition site, and a chymotrypsinrecognition site.

As used herein, a “pepsin recognition site” is any site in a polypeptidesequence that is experimentally shown to be cleaved by pepsin. In someembodiments it is a peptide bond after (i.e., downstream of) an aminoacid residue selected from Phe, Trp, Tyr, Leu, Ala, Glu, and Gln,provided that the following residue is not an amino acid residueselected from Ala. Gly, and Val.

As used herein, a “trypsin recognition site” is any site in apolypeptide sequence that is experimentally shown to be cleaved bytrypsin. In some embodiments it is a peptide bond after an amino acidresidue selected from Lys or Arg, provided that the following residue isnot a proline.

As used herein, a “chymotrypsin recognition site” is any site in apolypeptide sequence that is experimentally shown to be cleaved bychymotrypsin. In some embodiments it is a peptide bond after an aminoacid residue selected from Phe, Tip, Tyr, and Leu.

Disulfide bonded cysteine residues in a protein tend to reduce the rateof digestion of the protein compared to what it would be in the absenceof the disulfide bond. For example, it has been shown that the rate ofdigestion of the protein b-lactoglobulin is increased when its disulfidebridges are cleaved (I. M. Reddy, N. K. D. Kella, and J. E. Kinsella.“Structural and Conformational Basis of the Resistance ofB-Lactoglobulin to Peptic and Chymotryptic Digestion”. J. Agric. FoodChem, 1988, 36, 737-741). Accordingly, digestibility of a protein withfewer disulfide bonds tends to be higher than for a comparable proteinwith a greater number of disulfide bonds. In some embodiments theproteins disclosed herein are screened to identify the number ofcysteine residues present in each and in particular to allow selectionof a protein comprising a relatively low number of cysteine residues.For example, edible species proteins or fragments can be identified thatcomprise a no Cys residues or that comprise a relatively low number ofCys residues, such as 10 or fewer Cys residues, 9 or fewer Cys residues,8 or fewer Cys residues, 7 or fewer Cys residues, 6 or fewer Cysresidues, 5 or fewer Cys residues, 4 or fewer Cys residues, 3 or fewerCys residues, 2 or fewer Cys residues, 1 Cys residue, or no Cysresidues. In some embodiments one or more Cys residues in an ediblespecies protein or fragment thereof is removed by deletion and/or bysubstitution with another amino acid. In some embodiments 1 Cys residueis deleted or replaced, 1 or more Cys residues are deleted or replaced,2 or more Cys residues are deleted or replaced, 3 or more Cys residuesare deleted or replaced, 4 or more Cys residues are deleted or replaced,5 or more Cys residues are deleted or replaced, 6 or more Cys residuesare deleted or replaced, 7 or more Cys residues are deleted or replaced,8 or more Cys residues are deleted or replaced, 9 or more Cys residuesare deleted or replaced, or 10 or more Cys residues are deleted orreplaced. In some embodiments the protein of this disclosure comprises aratio of Cys residues to total amino acid residues equal to or lowerthan 5%, 4%, 3%, 2%, or 1%. In some embodiments the protein comprises 10or fewer Cys residues, 9 or fewer Cys residues, 8 or fewer Cys residues,7 or fewer Cys residues, 6 or fewer Cys residues, 5 or fewer Cysresidues, 4 or fewer Cys residues, 3 or fewer Cys residues, 2 or fewerCys residues, 1 Cys residue, or no Cys residues. In some embodiments,the protein comprises 1 or fewer Cys residues. In some embodiments, theprotein comprises no Cys residues.

Alternatively or in addition, disulfide bonds that are or can be presentin a protein can be removed. Disulfides can be removed using chemicalmethods by reducing the disulfide to two thiol groups with reducingagents such as beta-mercaptoethanol, dithiothreitol (DTT), ortris(2-carboxyethyl)phosphine (TCEP). The thiols can then be covalentlymodified or “capped” with reagents such as iodoacetamide,N-ethylmaleimide, or sodium sulfite (see, e.g., Crankshaw, M. W. andGrant, G. A, 2001. Modification of Cysteine. Current Protocols inProtein Science. 15.1.1-15.1.18).

Nutritive Polypeptides and Nutritive Polypeptide Formulations withModulated Viscosity.

Disclosed herein are compositions, formulations, and food products thatcontain viscosity-modulating nutritive polypeptides. In one aspect,provided are formulations substantially free of non-comestible productsthat contain nutritive polypeptides present in a nutritional amount, andthe nutritive polypeptide decreases the viscosity of a food product. Insome embodiments, the nutritive polypeptide is present at about 10 g/land the viscosity of the formulation is from about 1,000 mPas to about10,000 mPas at 25 degrees C., such as from about 2,500 mPas to about5,000 mPas at 25 degrees C.

The formulations are incorporated into food products having advantagesover similar food products lacking the nutritive polypeptides, or theformulations are incorporated into other products such as beverageproducts or animal feed products. For example, the food products have areduced fat content, a reduced sugar content, and/or a reduced caloriecontent compared to a food product not having the nutritive polypeptide.Preferably, the nutritive polypeptide is present in the food productsuch that consumption of a nutritional amount of the food product issatiating. In an embodiment of the invention, gelatin, an animal-derivedmaterial, is replaced by a non-animal derived product, containing one ormore nutritive polypeptides. Typically the nutritive polypeptide ispresent in an amount effective to replace gelatin in the product. Thegelatin replacement is incorporated into a food product, a beverageproduct, or an animal feed product, and the formulation is substantiallyfree of non-comestible products.

Also provided are formulations containing a nutritive polypeptidepresent in a functional and/or nutritional amount, which increases theviscosity of a food or beverage product, such as formulations containingviscosity-increasing nutritive polypeptides incorporated into foodproducts having advantages over similar food products lacking thenutritive polypeptides. For example, the food products have a reducedfat content, a reduced sugar content, and/or a reduced calorie contentcompared to a food product not having the nutritive polypeptide. Viscousnutritive polypeptides can be used as a nutritionally favorable lowcalorie substitute for fat. Additionally, it may be desired to add tothe compositions and products one or more polysaccharides oremulsifiers, resulting in a further improvement in the creamy mouthfeel.

In some embodiments, the viscosity of nutritive polypeptide-containingmaterials is enhanced by crosslinking the nutritive polypeptides orcrosslinking nutritive polypeptides to other proteins present in thematerial. An example of an effective crosslinker is transglutaminase,which crosslinks proteins between an ∈-aminogroup of a lysine residueand a γ-carboxamide group of glutamine residue, forming a stablecovalent bond. The resulting gel strength and emulsion strength ofnutritive polypeptides identified and produced as described herein areexamined by preparing a transglutaminase-coupled nutritive proteincomposition, followed by gel strength and emulsion strength assays. Asuitable transglutaminase derived from microorganisms in accordance withthe teachings of U.S. Pat. No. 5,156,956 is commercially available.These commercially available transglutaminases typically have an enzymeactivity of about 100 units. The amount of transglutaminase (having anactivity of about 100 units) added to isolated nutritive polypeptide isexpressed as a transglutaminase concentration which is the units oftransglutaminase per 100 grams of isolated nutritive polypeptide. Theisolated nutritive polypeptide contains from 5 to 95%, preferably 20 to80%, preferably 58% to 72% protein and also preferably from 62% to 68%protein. The transglutaminase concentration is at least 0.15, preferably0.25 and most preferably 0.30 units transglutaminase per gram protein upto 0.80 and preferably 0.65 units transglutaminase per gram protein.Higher and lower amounts may be used. This enzyme treatment can also befollowed by thermal processing to make a viscous solution containing anutritive polypeptide. To generate nutritive polypeptide samplescontaining crosslinks, a sample is mixed with a transglutaminasesolution at pH 7.0 to give an enzyme to protein weight ratio of 1:25.The enzyme-catalyzed cross-linking reaction is conducted at 40° C. inmost of the experiments.

Oscillatory shear measurements can be used to investigate therheological properties of nutritive polypeptides. Also, to determine theviscosity of nutritive polypeptide solutions and gels viscoelasticity isinvestigated by dynamic oscillatory rheometry. A 2 mL sample ofnutritive polypeptide solution or nutritive polypeptide solutioncontaining transglutaminase is poured into the Couette-type cylindricalcell (2.5 cm i.d., 2.75 cm o.d.) of the rheometer and covered with athin layer of low-viscosity silicone oil to prevent evaporation. Forsamples with enzyme present, gelation is induced in situ by incubationat 40° C. For nutritive polypeptide samples without enzyme, gelation isinduced by subjecting the sample to the following thermal treatmentprocess: temperature increased at constant rate of 2 K min-1 from 40 to90° C., kept at 90° C. for 30 min, cooled at 1 K min-1 from 90 to 30°C., and kept at 30° C. for 15 min. Some samples can be subjected to thisthermal treatment after the enzyme treatment. Small deformation shearrheological properties are mostly determined in the linear viscoelasticregime (maximum strain amplitude 0.5%) with storage and loss moduli (G′and G″) measured at a constant frequency of 1 Hz. In addition, somesmall deformation measurements are made as a function of frequency e.g.,2×10-3 to 2 Hz, and some large deformation measurements are carried outat strains up to nearly 100%.

Nutritive Polypeptides for Increasing Renal Function and Treatment andPrevention of Renal Diseases

Provided are nutritive polypeptides, and compositions and formulationscontaining nutritive polypeptides, which are useful for increasing renalfunction and treatment and prevention of renal diseases. The nutritivepolypeptides are also useful for treating and preventing loss of musclemass and muscle function in a subject, particularly a subject undergoingtreatment for a renal disease. Moreover, the nutritive polypeptides arefurther useful for reducing or preventing a side effect (meaning asecondary effect, usually undesirable, of a pharmaceutical agent ormedical treatment) of therapeutic or prophylactic regimens for renaldisease treatment, as such regimens may result in decreased amino acidavailability to the subject, in addition to causing loss of muscle massand muscle function.

Provided are nutritive polypeptides, and compositions and formulationscontaining nutritive polypeptides, which are useful for the treatmentand prevention of kidney diseases, particularly those suffering fromchronic kidney disease (CKD) and urea cycle disorders. As used herein, a“chronic kidney disease” includes any pathological condition such thatone or both of a subject's kidneys are damaged and cannot filter bloodcomparable to a healthy kidney. A “urea cycle disorder” includes anydeficiency in one or more of the enzymes or transporters that areinvolved in the urea cycle.

The CDC estimates that more than 10% of adults in the United States mayhave CKD, of varying levels of seriousness (CDC, US Department of Healthand Human Services, Centers for Disease Control and Prevention (2014)).The likelihood of having CKD increases with age and is most common amongadults older than 70 years. Deterioration of the kidneys leads to kidneyfailure, a type of CKD where waste is no longer effectively removed fromthe blood. Kidney failure is also called end-stage renal disease (ESRD).In 2011, 113, 136 patients in the United States started treatment forend stage renal disease. Health related consequences of CKD are swellingin the arms and legs, high blood pressure, pulmonary edema,pericarditis, hyperkalemia, weakened bone strength, anemia, weakenedimmune system, depression, and malnourishment. A reduction or preventionof each of these consequences is useful to demonstrate efficacioustreatment using nutritive polypeptides.

Exemplary kidney diseases include Alport Syndrome, Diabetic Nephropathy,Fabry Disease, Focal Segmental Glomerulosclerosis, Glomerulonephritis,IgA Nephropathy, Kidney Stones. Minimal Change Disease, NephroticSyndrome, and Polycystic Kidney Disease.

Exemplary urea cycle disorders include NAGS deficiency.Carbamoylphosphate synthetase I deficiency, Ornithine transcarbamylasedeficiency, Citrullinemia type I, Argininosuccinic aciduria, Arginasedeficiency, Ornithine Translocase Deficiency, (Summar, et al.GeneClinics: Medical Genetics Knowledge Base. Seattle, University ofWashington (2005)).

Subjects with CKD undergo damage to the kidneys that results indecreased kidney function, and as kidney function deteriorates, wasteproducts build to high levels in blood and diminish health.Complications associated with chronic kidney disease include high bloodpressure, anemia (low blood count), weak bones, poor nutritional healthand nerve damage. As a result, subjects have an increased risk of havingheart and blood vessel disease. Maintaining subject and kidney healthprevents or slows progression of disease to kidney failure, whichrequires dialysis or a kidney transplant to maintain life. As a resultof inadequate metabolic and nutritional status, high mortality andmorbidity rates remain prevalent in patients suffering from CKD,particularly in those with ESRD receiving dialysis. This altered status,deemed protein energy wasting (PEW), is often caused by inadequatedietary protein intake and amino acid utilization, and has a significanteffect on subject mortality rate. Dialysis depletes the body of aminoacids, and the compromised kidneys alter amino acid homeostasis in thehuman body. PEW generally results in loss of muscle and protein stores,compounding the effects of renal disease. To limit the effects of PEW,attempts have been made to optimize dietary nutrient intake, and provideappropriate treatment of metabolic disturbances such as metabolicacidosis, systemic inflammation, and hormonal deficiencies, andoptimized dialytic regimens. (See, e.g., Ikikier, T. et al. Kidneyinternational 84.6 (2013): 1096-1107). In patients where oral dietaryintake is insufficient, enteral or parenteral nutrition supplementationis required to replenish protein and energy stores. A nutritionalpolypeptide formulation as described herein, provides a effectivecomposition and formulation to prevent and treat PEW. These treatmentsare beneficially combined with exercise.

Uremic toxicity, where excess nitrogenous waste products exist incirculation often occurs in CKD and, must be monitored. CKD patients aresometimes placed on a low protein diet to prevent uremic toxicity. Urea,the main nitrogenous metabolite from ingestion of protein, may or maynot be toxic alone, and can serve as an indicator of accumulation ofother toxins as a consequence of altered renal function.

CKD patients are known to have abnormal amino acid profiles in serum, inparticular, low levels of essential amino acids (EAAs) and branchedchain amino acids (BCAAs). For example. Kim et. al. report lower serumBCAAs levels in ESRD dialysis patients compared to a control group. Morespecifically, lower levels of serine, tyrosine and lysine as well as theBCAAs-valine, leucine and isoleucine have been reported (Kim, D. H. Kor.Journ. Int. Med. 1998, 13(1): 33-40). Therefore, BCAA-enriched nutritivepolypeptides and/or EAA-enriched nutritive polypeptides are ofparticular utility for patients with CKD.

Moreover, it has been shown that supplementation of free BCAAs in thediet can improve the nutritional status and appetite of dialysispatients. (Hiroshige, K. Nephr. Dial. Transplant. 2001, 16:1856-62).Levels of BCAAs were normalized by 12 g/day oral supplements. Nutritivepolypeptides high in BCAAs are an effective treatment for patientscompromised by renal disease. PEW can be remedied by restoring thespecific amino acids lost by dialysis and diminished metabolic functionby nutritive polypeptide administration while diminishing stress on analready compromised patient. A nutritive polypeptide selected forimproving the status of ESRD patients, particularly those with PEW,delivers effective combinations of amino acids at a beneficial quantity,and in a formulation that results in high compliance. Specifically, anutritive polypeptide high in BCAAs satisfies these requirements.Optionally, the nutritive polypeptide is low in glutamine and glutamicacid content, since patients with renal disease do not efficientlyexcrete ammonia, a by-product of glutamic acid and glutamine metabolism.Accumulation of ammonia in the blood, also known as hyperammonemia, is adangerous condition that may lead to death (See, e.g., Sacks, G. S. Ann.Pharmacol. 1999, 33:348-354).

Uremic toxicity, where excess nitrogenous waste products exist incirculation, is prevalent in CKD and should be monitored. In order toprevent uremic toxicity, nutritive formulations are administered to CKDsubjects; currently, CKD patients are sometimes placed on a low proteindiet to prevent uremic toxicity, which results in decreased amino acidavailability, muscle loss, and other effects of decreased amino acidlevels. Urea, the main nitrogenous metabolite from ingestion of protein,is a useful indicator of accumulation of other toxins as a consequenceof altered renal function. Thus, a nutritive polypeptide is able todeliver amino acids effectively to meet a subject's nutritional needs,while diminishing risks of these side effects. In particular, a highBCAA protein satisfies these requirements. Whereas some ESRD patientsare placed on a low protein diet, in contrast dialysis patients areplaced on a high protein diet due to loss of amino acids that occurduring the dialysis process. Hyperphosphatemia is a complication of apoorly optimized high protein diet, where high phosphorous levels fromfood can become toxic in individuals with CKD (Mandayam, S. Nephrology.2006, 11:53-57). Even mild increases in serum phosphorous levelsincreased mortality rates in CKD patients (Kestenbaum, B. J. Am. Soc.Nephrol. 2005, 16: 520-28). A nutritive polypeptide is advantageous inCKD, as it counteracts the loss of amino acids, while sparing thekidneys of extraneous dietary phosphorous.

Patients with urea cycle disorders have genetic mutations that result ina deficiency of one of the enzymes or transporters that are involved inthe urea cycle, which are responsible for removing ammonia from theblood. Disrupting the urea cycle limits the removal of nitrogen from theblood by converting it into urea and transferring to the urine. Theaccumulation of nitrogen in the blood causes an increase in ammonia(hyperammonemia). Ammonia is highly toxic and can cause irreversiblebrain damage, coma, and possibly death. In some embodiments, thenutritive polypeptides provided herein are useful to lower creatinineand urine osmolality.

Urea cycle disorder (UCD) patients are treated or symptoms prevented byadministration of nutritive polypeptides. The urea cycle is the mainnitrogenous waste disposal pathway in humans. UCD is a hereditarydisorder caused by deficiency of one or more enzymes in the cycle,ultimately resulting in hyperammonemia. UCD patients present low BCAAserum levels. (Boneh, A. Mol. Genet. Metab. 2014. S1096-7192).Disruption of the normal urea cycle causes diminished synthesis ofarginine, normally a nonessential amino acid (Leonard, J. V. Journ.Pediatrics. 2001, 138(1):S40-45). Arginine plays a major role in theurea cycle. The synthetic pathway of arginine interacts closely with theurea cycle enzymes in the liver and kidneys, and is made from omithinevia citrulline (Barbul A. J Parenter Enteral Nutr. 1986, 10: 227-238).Citrulline and ornithine are required to be supplemented in UCDpatients: however, they are not found in natural proteins and are notgenerally present in nutritive polypeptides. A nutritive polypeptideindicated for urea cycle disorders contains high levels of BCAAs andarginine. Supplementation of glutamine and glutamic acid produces thenitrogenous waste product ammonia, so a nutritive polypeptide useful forUCD is generally low in these amino acids. A nutritive polypeptideprovides an optimized therapy for UCD patients, as it can deliveressential amino acids such as the BCAAs, as well as arginine, withoutdelivering excess free amino acids.

Amino Acid Pharmacology.

Amino acids are organic molecules containing both amino and acid groups.All amino acids have asymmetric carbon except for glycine and allprotein amino acids, except proline, have an alpha-carbon bound to acarboxyl group and a primary amino group.

Amino acids exhibit a diverse range of biochemical properties andbiological function due to their varying side chains. They are stable insolution at physiological pH, save for glutamine and cysteine. In thecontext of some proteins, conditional upon the host and translationalmachinery, amino acids can undergo post-translational modification. Thiscan have significant effects on their bioavailability, metabolicfunction, and bioactivity in vivo. Sugar moieties appended to proteinspost-translationally may reduce the usefulness of the nutritive proteinsby affecting the gastrointestinal release of amino acids and embeddedpeptides. A comparison of digestion of glycosylated and non-glycosylatedforms of the same proteins shows that the non-glycosylated forms aredigested more quickly than the glycosylated forms (our data).

Although over 300 amino acids exist in nature, 20 serve as buildingblocks in protein. Non-protein alpha-AAs and non-alpha AAs are directproducts of these 20 protein amino acids and play significant roles incell metabolism. Due to the metabolic reactions of amino acid catabolismthat drive the interconversion between amino acids, a subset of 11 ofthe 20 standard protein amino acids are considered non-essential forhumans because they can be synthesized from other metabolites (aminoacids, ketones, etc.) in the body: Alanine; Arginine; Asparagine;Aspartic acid; Cysteine; Glutamic acid; Glutamine; Glycine; Proline;Serine; and Tyrosine.

Arginine, cysteine, glycine, glutamine, histidine, proline, serine andtyrosine are considered conditionally essential, as they are notnormally used in the diet, and are not synthesized in adequate amountsin specific populations to meet optimal needs where rates of utilizationare higher than rates of synthesis. Functional needs such asreproduction, disease prevention, or metabolic abnormalities, however,can be taken into account when considering whether an amino acid istruly non-essential or can be conditionally essential in a population.The other 9 protein amino acids, termed essential amino acids, are takenas food because their carbon skeletons are not synthesized de novo bythe body to meet optimal metabolic requirements: Histidine; Isoleucine;Leucine; Lysine; Methionine; Phenylalanine; Threonine; Tryptophan: andValine.

All 20 protein amino acids (and non-protein metabolites) are used fornormal cell functionality, and shifts in metabolism driven by changingavailability of a single amino acid can affect whole body homeostasisand growth. Additionally, amino acids function as signaling moleculesand regulators of key metabolic pathways used for maintenance, growth,reproduction, immunity.

In the body skeletal muscle represents the largest store of both freeand protein-bound amino acids due to its large composition of body mass(around 40-45%). The small intestine is another important site for aminoacid catabolism, governing the first pass metabolism and entry ofdietary amino acids into the portal vein and into the peripheral plasma,30-50% of EAA in the diet may be catabolized by the small intestine infirst-pass metabolism. The high activity of BCAA transaminases in theintestinal mucosa leads to BCAA conversion to branched-chainalpha-ketoacids to provide energy for enterocytes similar as is done inskeletal muscle. Differences in physiological state of muscle and smallintestine metabolism have large implications on amino acid biologysystemically across tissues in humans.

Amino acids can exist in both L- and D-isoforms, except for glycine(non-chiral). Almost all amino acids in proteins exist in the L-isoform,except for cysteine (D-cys) due to its sulfur atom at the secondposition of the side-chain, unless otherwise enzymaticallypostranslationally modified or chemically treated for storing or cookingpurposes. Most D-amino acids, except for D-arg, D-cys, D-his, D-lys, andD-thr, can be converted into the L chirality by D-AA oxidases andtransaminases. In order to be catabolized, these D enantiomers aretransported across the plasma and other biological membranes and undergoD-oxidation or deaminate the amino acid to convert to its alpha-ketoacidor racemization to convert the D-AA to its L-isoform. The transport ofD-isomers is limited by a lower affinity of L-AA transporters to D-AAs.For this reason the efficiency of D-AA utilization, on a molar basis ofthe L-isomer, can range from 20-100% depending on the amino acid and thespecies.

Alanine:

Alanine is a glucogenic non-essential amino acid due to its ability tobe synthesized in muscle cells from BCAAs and pyruvate as part of theglucose-alanine cycle. This involves a tightly regulated process bywhich skeletal muscle frees energy from protein stores for thegeneration of glucose distally in the liver for use by extrahepaticcells (including immunocytes) and tissues. The resulting stimulation ofgluconeogenesis provides a source of energy in the form of glucoseduring periods of food deprivation. Alanine becomes a very sensitiveintermediary to balance the utilization of BCAAs in the muscle forprotein production and generation of available energy throughgluconeogenesis in the liver. Furthermore, the alanine induction ofgluconeogenesis is integral to support the function of many tissues, notlimited to muscle, liver, and inmmunocytes. Beyond acting as simply anintermediate, however, it also directly regulates activity of a keyenzyme in this energy balance, pyruvate kinase. Alanine has the abilityto inhibit pyruvate kinase by facilitating its phosphorylation, slowingglycolysis and driving the reverse reaction of pyruvate tophosphoenolpyruvate (PEP) for initiation of gluconeogenesis.

High Alanine

A lack of ATP-producing substrates, as occurs in a fasted state, canlead to autophagy and the turnover of intracellular protein in thelysosome to provide an energy source. Low levels of the glucogenic aminoacids, including alanine can stimulate hepatic autophagy, leading todegradation of liver function.

Beta-cells show increased autophagy when under high fat diet feeding asa response to increased demand for insulin production and proteinturnover as the body reacts to rising plasma glucose concentrations.This progression towards increased insulin production in obesity is anearly marker for pre-diabetes, an indicator of insulin resistance, and arisk factor for the deterioration of islet beta cell functionality whicheventually leads to the onset of diabetes in overweight individuals. Theability to regulate alanine levels via nutrition may provide a powerfullever for shifting hepatic and beta cell autophagy to perturb impairedinsulin metabolism in overweight individuals.

Alanine directly produces beta-alanine, important to the biosynthesis ofpanthothenic acid (vitamin b5), coenzyme A, and carnosine (or which itis the rate-limiting precursor). Carnosine, as well as otherbeta-alanine derived di-peptides (which don't incorporate into proteins)carcinine, anserine, and balenine act as antioxidant buffers in themuscle tissue, constituting up to 20% of the buffer capacity in type Iand II muscle fibres. This buffering is important for maintaining tissuepH in muscle during the breakdown of glycogen to lactic acid. In weightloss/gain trials in college athletes, supplementation with beta-alaninewas shown to prevent loss of lean mass in weight loss and largerincreases in lean mass during weight gain compared to placebo.Beta-alanine is also implicated in decreasing fatigue and increasingmuscular work done.

Carnosine is an antioxidant and transition metal ion-sequestering agent.It acts as an anti-glycating agent by inhibiting the formation ofadvanced glycation end products (AGEs). AGEs are prevalent in diabeticvasculature and contribute to the development of atherosclerosis. Thepresence of AGEs in various cells types affect both the extracellularand intracellular structure and function. (Golden, A. et. al. AdvancedGlycosylation End Products. Circulation 2006). Also, the accumulation ofAGEs in the brain is a characteristic of aging and degeneration,particularly in Alzheimer's disease. AGE accumulation explains manyneuropathological and biochemical features of Alzheimer's disease suchas protein crosslinking, oxidative stress, and neuronal cell death.Because of its combination of antioxidant and antiglycating properties,carnosine is able to diminish cellular oxidative stress and inhibit theintracellular formation of reactive oxygen species and reactive nitrogenspecies.

Low Alanine

In states of obesity and diabetes, animals have been shown to exhibitreduced hepatic autophagy, leading to increased insulin resistance.Autophagy is important for maintenance of the ER and cellularhomeostasis, which when stressed can lead to impaired insulinsensitivity. High fat diet feeding in animal models stresses the ER,while leading to depressed hepatic autophagy through over-stimulation ofmTORC1, which reinforces the progression towards insulin sensitivityimpaired beta cell function in diabetes. Reducing the level of systemicAlanine provides an opportunity to lower mTORC1 activity and restorehealthy levels of autophagy.

Arginine:

Arginine is a glucogenic non-essential amino acid, which can besynthesized via glutamate, aspartate, glutamine, and proline. It isproduced by the mammalian small intestine via oxidation of glutamate,glutamine, and aspartate, which generates ornithine, citrulline,arginine, and alanine. It can also be produced (along with ornithine andcitrulline) via the proline oxidase pathway from active degradation ofproline in enterocytes. Arginine is converted from citrulline releasedinto circulation by the enterocytes in the kidneys and some endothelialcells (leukocytes and smooth muscle). Newborns utilize most of the freecitrulline locally in the small intestine for arginine synthesis ratherthan systemic release. Arginine and proline oxidation is constrained tothe mucosa due to reduced activity of pyrroline-5-carboxylatedehydrogenase across the other tissues.

High Arginine

Citrulline is produced from arginine as a by-product of a reactioncatalyzed by the NOS family. Dietary supplement of either arginine orcitrulline is known to reduce plasma levels of glucose, homocysteine,and asymmetric dimethylarginine, which are risk factors for metabolicsyndrome. L-citrulline accelerates the removal of lactic acid frommuscles, likely due to the affects on vascular tone and endothelialfunction. Recent studies have also shown that L-citrulline fromwatermelon juice provides greater recovery from exercise, and lesssoreness the next day. It also appears that delivery of L-citrulline asa free form results in less uptake into cells in vitro than in thecontext of watermelon juice (which contains high levels ofL-citrulline). This suggests an opportunity to deliver peptide doses,which can traffic arginine into muscle tissue for conversion intocitrulline by eNOS at the endothelial membrane for improved efficacy.

Arginine is a highly functional amino acid implicated in many signalingpathways and as a direct precursor of nitric oxide (NO), whichfacilitates systemic signaling between tissues and regulation ofnutrient metabolism and immune function. NO is important for normalendothelial function and cardiovascular health (including vascular tone,hemodynamics, and angiogenesis). Arginine stimulates insulin secretionby directly depolarizing the plasma membrane of the β cell leading tothe influx of Ca²⁺ and subsequent insulin exocytosis.

Arginine supplementation was shown to improve endothelium-dependentrelaxation, an indicator of cardiovascular function in type I and typeII models of diabetes mellitus. Notably, arginine supplementationreduced white adipose tissue but increased brown fat mass in Zuckerdiabetic rats and diet-induced obese rats. Arginine and/or itsmetabolites may enhance the proliferation, differentiation, and functionof brown adipocytes. In addition, both skeletal muscle mass and wholebody insulin sensitivity were enhanced in response to argininesupplementation via mechanisms involving increases in muscle mTOR and NOsignaling. Surprisingly, long-term oral administration of argininedecreased fat mass in adult obese humans with type II diabetes (Lucottiet al 2006). Moreover, supplementation with arginine to a conventionalcorn- and soybean-based diet reduced fat accretion and promoted proteindeposition in the whole body of growing-finishing pigs. In a small pilottrial in humans data indicated that defective insulin-mediatedvasodilatation in obesity and non-insulin dependent diabetics (NIDDM)can be normalized by intravenous L-arginine; L-arginine also improvedinsulin sensitivity in healthy subjects, obese patients and NIDDMpatients, indicating a possible mechanism that is different from therestoration of insulin-mediated vasodilatation. In addition, a chronicadministration of L-arginine improved glucose levels, insulininduced-hepatic glucose production, and insulin sensitivity in type IIdiabetic patients (Piatti et al 2001). Arginine rich peptides have notbeen isolated and tested.

Amino acid administration at high doses (10-20× that available in diet,or 0.3 g/kg body weight dosed over 20 minutes, via intravenous or oralroutes, can stimulate hormone secretion from the gut via endocrinecells. Arginine is a well-studied secretagogue that can stimulate thesystemic release of insulin, growth hormone, prolactin, glucagon,progesterone, and placental lactogen. This biology has directimplications on both digestive biology and the absorption of nutrientspresent in the intestine, as well as affecting energy balance bytriggering satiety signals mediated by endocrine hormones. The abilityto modulate these hormones provides a therapeutic opportunity fordecreasing caloric intake in metabolic disorders such as obesity oralternatively triggering appetite in muscle wasting, sarcopenia, andcachexia, as well as by shifting insulin sensitivity in the onset ofdiabetes.

Arginine is an important signaling molecule for stimulating mTOR1phosphorylation in a cell-specific manner. This regulates cellularprotein turnover (autophagy) and integrates insulin-like growth signalsto protein synthesis initiation across tissues. This biology has beendirectly linked to biogenesis of lean tissue mass in skeletal muscle,metabolic shifts in disease states of obesity and insulin resistance,and aging. It is also a central signaling pathway which can be hijackedfor the proliferation of fast-growing cancer cells.

There is evidence for Arginine increasing levels of protein synthesis inthe small intestine under catabolic states such as viral infection andmalnutrition, where amino acid levels are dramatically shifted fromtheir normal post-absorptive states. Additionally, demonstrated mTORactivation in the intestinal epithelial cells by Arginine provides amechanism to repair intestinal epithelium by stimulating proteinsynthesis and cell proliferation. Similar anabolic signaling has beenobserved in myocytes in response to rising plasma levels of Arginine,leading to increased whole body and skeletal muscle protein synthesis.Arginine is an amino acid maintained at sufficient levels to support theanabolic effects of EAAs. Lysine, Methionine. Threonine. Tryptophan.Leucine, Isoleucine, and Valine have been shown unable to supportincreased protein synthesis and whole-body growth when added to a 12.7%crude protein diet, indicating a deficiency in the anabolic mediatingnon-essential amino acids, including Arginine.

Arginine also up-regulates proteins and enzymes related to mitochondrialbiogenesis and substrate oxidation, stimulating metabolism of fatty acidstores and reducing fat tissue mass. Supplementation of dietary Arginineprovides a therapeutic benefit in obese and pre-diabetic populations whosuffer from insulin resistance due to their increased caloric intake.Likewise, the ability to stimulate mitochondrial biogenesis has directimplications in aging and the ability to regenerate functional proteinsand healthy cells subject to oxidative stress.

It is established that dietary deficiency of protein reduces theavailability of most amino acids, including Arginine despite it notbeing considered essential. Arginine deficiency is known to causedecreases in sperm counts by 90% after 9 days, increasing the proportionof non-motile sperm by a factor of 10. Arginine supplementation has beendemonstrated in animals to increase levels of Arginine, Proline,Ornithine, and other Arginine metabolites such as Polyamines in seminalfluid, corresponding with increased sperm counts and sperm motility.Changes in NO synthesis and polyamines (via), likewise are seen duringgestation when placental growth rate peaks, indicating a role forArginine in fetal development during pregnancy. In uterine fluids duringearly gestation Arginine levels also decrease in response to expressionof specific amino acid transporters at the embryo. Argininesupplementation to the diet of animals during early gestation has shownembryonic survival and increase in litter size, indicating a significantpotential for delivering high levels of arginine during pregnancy.

Arginine has an extensively studied effect on enhancing immune function,based on direct effects on NO production (which can potentiate aphagocyte's killing ability), hormonal secretagogue activity, andstimulation of mTOR. Proline catabolism by proline oxidase is known tohave high levels of activity in the placentae and small intestine ofmammals. This activity points to a crucial role for Arginine in gut andplacentae immunity, both through generation of H₂O₂, which is cytotoxicto pathogenic bacteria, and synthesis of arginine. In critically injuredpatients leukocyte count normalizes more quickly after 6 days ofArginine enriched diet, with recovery to normal TNF response after 10days (100% improvement). A clinical study in 296 surgery, trauma, orsepsis patients examining Arginine enriched (12.5 g/L Arginine)formulation vs enteral formula indicates highly reduced hospital stay(8-10 days) and major reduction in frequency of acquired infections. Aseparate clinical study of 181 septic patients fed Arginine enriched(12.5 g/L Arginine) vs. enteral formula show significantly reducedbacteremia (8% vs 22%), nosocomial infection (6% vs 20%).

Arginine is also a key substrate for the synthesis of collagen. Oralsupplementation of arginine enhances wound healing and lymphocyte immuneresponse in healthy subjects. A 2.4× increase in collagen deposition wasobserve at wound sites (24 nmol/cm vs. 10.1 nmol/cm), along withincreased lymphocyte proliferation vs. control.

Arginine is an allosteric activator of N-acetylglutamate synthase, anenzyme which converts glutamate and acetyl-CoA into N-acetylglutamate inthe mitochondria. This pushes the hepatic urea cycle towards the activestate, useful for ammonia detoxification. This means that dietarydelivery of nutrients with low doses of arginine may be useful in thecontext of kidney disease, where patients struggle to clear urea fromtheir circulation. Elimination of arginine to limit uremia from theavailable nitrogen sources, while being able to maintain a limitedprotein intake to prevent tissue catabolism, is a novel strategy againsta disruptive nutritional consequence of kidney disease.

Arginine up-regulates the activity of GTP cyclohydrolase-I, freeingtetrahydrobiopterin (THB) for NO synthesis and the hydroxylation ofaromatic amino acids (ArAAs) by aromatic amino acid hydroxylase (AAAH).For this reason, delivery of high levels of Arginine to raise cellularlevels of THB directly stimulates the biosynthesis of manyneurotransmitters in the CNS capillary endothelial cells. ArAAs serve asprecursors for biosynthesis of monoamine neurotransmitters, includingmelatonin, dopamine, norepinephrine (noradrenaline), and epinephrine(adrenaline).

Low Arginine

Excessive arginine intake, stimulating production of high levels of NOin the blood can lead to oxidative injury and apoptosis of cells.

Arginine excess or depletion affects global gene expression in mammalianhepatocytes. Depletion leads to 1419 genes with significantly (p<0.05)altered expression using in-vitro models, of which 56 showed at least2-fold variation using a 9-way bioinformatics analysis. The majorityrise in expression, including multiple growth, survival, andstress-related genes such as GADD45. TA1/LAT1, and caspases 11 and 12.Many are relevant in luminal ER stress response. LDLr, a regulator ofcholesterol and steroid biosynthesis, was also modulated in response toarginine depletion. Consistent with Arginine affecting gene expression,dietary arginine supplementation up-regulates anti-oxidative genes andlowers expression of proinflammatory genes in the adipose and smallintestinal tissues.

Lower arginine levels inhibit neurotransmitter biosynthesis, which hasshown clinical efficacy in indications such as mania, parkinsons, anddyskenisia.

Asparagine:

Asparagine is a glucogenic nonessential amino acid, whose precursor isoxaloacetate (OAA) and which is synthesized via glutamine and aspartateby a transaminase enzyme. It is used for the function of some neoplasticcells such as lymphoblasts.

Asparagine is typically located at the ends of alpha helices of proteinsand provides important sites for N-linked glycosylation to addcarbohydrate chains, which affects immune response to amino acidingestion.

Acyrlamide is formed by heat-induced reactions between Asparagine andcarbonxyl groups of glucose and fructose in many plant-derived foods.Acrylamide is an oxidant that can be cytotoxic, cause gene mutations,and generally affect food quality. Compositions with low levels ofasparagine are useful in making safer food products that may be subjectto cooking or non-refrigerated storage conditions.

Aspartate:

Aspartate is a glucogenic nonessential amino acid synthesized via theoxaloacetate (OAA) precursor by a transaminase enzyme. As part of theurea cycle, it can also be produced from ornithine and citrulline (orarginine) as the released fumarate is converted to malate andsubsequently recycled to OAA. Aspartate provides a nitrogen atom in thesynthesis of inosine, which is the precursor in purine biosynthesis. Itis also involved in the synthesis of beta-alanine. Aspartate oxidizes inenterocytes of the small intestine, leading to nitrogeneous productsornithine, citrulline, arginine, and alanine.

Aspartate is an agonist of NMDA receptors (Glutamate receptors),releasing Ca2+ as a second messenger in many cellular signalingpathways. There are dopaminergic and glutaminergic abnormalitiesimplicated in schitzophrenia, with NMDA antagonists mimicking somepositive and negative symptoms of schitzophrenia, while carrying lessrisk of brain harm than do dopamine agonists. Ketamine and PCP, forexample, produce similar phenotypes observed in schitzophrenia, with PCPshowing less representative symptomology yet similar brain structurechanges. Glutamate receptors have increased function, contributing tothe onset of schizophrenia. An increased proportion of post-synapticglutamate receptors to pre-synaptic glutamate receptors result inincreased glutamate signaling. Both agonizing and antagonizing NMDAreceptors has shown some benefit in treating Alzheimer's dementia,depending on the MOA and receptor specificity. Thus delivering proteinswith either high or low levels of Aspartate, which also as NMDA agonistactivity, could be therapeutic for this patient population. Proteinswith low levels of Aspartate would likely provide a synergistic benefitalong side NMDA antagonists, such as Memantine. Likewise, clinicaltrials on LY2140023 have demonstrated glutamate-based treatments ashaving potential for treating schizophrenia without the side effectsseen with xenochemical anti-psychotics. Similar studies combiningco-agonist glycine with anti-psychotics, showed improved symptomology,suggesting that delivering high doses of Aspartate, also a NMDA agonist,will yield similar therapeutic benefits in this patient population.

Aspartate is an acidic amino acid, with a low Pka of 3.9. Aspartate inthe dipeptide form with phenylalanine via a methyl ester yieldsaspartame, which is used as a commercial artificial sweetener.

Cysteine:

Cysteine is a nonessential amino acid, and is synthesized fromhomocysteine, which is itself synthesized from the metabolism ofmethionine. Serine is involved in cysteine's synthesis by condensingwith homocysteine to form cystathionine. Cystathionine is thendeaminated and hydrolyzed to form cysteine and alpha ketobutyrate.Cysteine's sulfur comes from homocysteine, but the rest of the moleculecomes from the initial serine residue. The biosynthesis of cysteineoccurs via a different mechanism in plants and prokaryotes. Cysteine isa vital amino acid because it plays an important role in proteinfolding. The disulfide linkages formed between cysteine residues helpsto stabilize the tertiary and quaternary structure of proteins, andthese disulfide linkages are most common among the secreted proteins,where proteins are exposed to more oxidizing conditions that are foundin the cellular interior. Despite the benefits of homocysteine, havinghigh systemic levels is a risk factor for developing cardiovasculardisease. Elevated homocysteine may be caused by a genetic deficiency ofcystathionine beta-synthase and excess methionine intake may be anotherexplanation. Control of methionine intake and supplementation with folicacid and vitamin B12 in the diet has been used to lower homocysteinelevels. Furthermore, because the availability of cysteine is a keycomponent that limits the synthesis of glutathionine, dietarysupplementation with N-acetyl-cysteine, a precursor for cysteine, ishighly effective in enhancing immunity under a wide range of diseasestates.

Cysteine undergoes rapid oxidation to Cystine. It facilitates thebiosynthesis of glutathionine, a powerful antioxidant which can donate areducing equivalent to unstable molecules such as reactive oxygenspecies (ROS) free radicals. After reducing an oxidative species, it canform a glutathionine sulfide with another reactive glutathionine,providing a mechanism of depleting oxidative stress inducing moleculesfrom cells (The liver can maintain concentrations of up to 5 mM).Glutathionine is a powerful neutralizer of toxins in the liver, andhelps to protect the liver from the damaging effects of toxins.Additionally, this detoxifying ability helps to diminish muscleweakness, prevents brittle hair, and protects against radiationassociated with these toxins. As a result, it is beneficial for thosesuffering from chemical allergies or exposed to high levels of airpollution. Glutathionine also is a cofactor for iNOS, allow maximalsynthesis of NO in the arg-NO pathway. NO is important for normalendothelial function and cardiovascular health (including vascular tone,hemodynamics, angiogenesis).

In addition to being a precursor to glutatithionine, cysteine is aprecursor for the H2S, which can induce endothelial-dependentrelaxation, and can be further converted to cysteine sulfinate. Cysteinesulfunate can be converted to taurine, which has the ability to decreasemethionine uptake. An excess of methionine increases the risks of thedevelopment of atherosclerosis by inducing hyperhomocysteinemia becausehomocysteine is an intermediate between methionine and cysteine.However, it is not known whether cysteine decreases homocysteinedirectly or through the reduction of methionine (Sebastiaan Wesseling,et al., Hypertension. 2009 53: 909-911).

Furthermore. Cysteine is a precursor for Taurine, which modulates thearginine-NO pathway. Taurine has several potentially protective effects.First, taurine has the ability to reduce oxidative stress by binding tohypochlorite. It has been hypothesized that taurine conjugates tomitochondrial transfer RNA, and in so doing, prevents the formation ofmitochondrial superoxide. Additionally, taurine inhibitshomocysteine-induced stress of the endoplasmic reticulum of vascularsmooth muscle cells and thus restores the expression and secretion ofextracellular superoxide dismutase.

Glutamate:

Glutamate oxidizes in enterocytes of the small intestine, leading tonitrogeneous products ornithine, citrulline, arginine, and alanine.Glutamate also modulates the arginine-NO pathway. NO is important fornormal endothelial function and cardiovascular health (includingvascular tone, hemodynamics, angiogenesis).

High Glutamate

A lack of ATP-producing substrates, as occurs in a fasted state, canlead to autophagy and the turnover of intracellular protein in thelysosome to provide an energy source. Low levels of the glucogenic aminoacids, including glutamate can stimulate hepatic autophagy, leading todegradation of liver function.

Citrulline is produced from Glutamate as a by-product of a reactioncatalyzed by the NOS family. Dietary supplement of citrulline is knownto reduce plasma levels of glucose, homocysteine., and asymmetricdimethylarginine, which are risk factors for metabolic syndrome.L-citrulline accelerates the removal of lactic acid from muscles, likelydue to the effects on vascular tone and endothelial function. Recentstudies have also shown that L-citrulline from watermelon juice providesgreater recovery from exercise, and less soreness the next day. It alsoappears that delivery of L-citrulline as a free form results in lessuptake into cells in vitro than in the context of watermelon juice(which contains high levels of L-citrulline). This suggests anopportunity to deliver peptide doses, which can traffic arginine intomuscle tissue for conversion into citrulline by eNOS at the endothelialmembrane for improved efficacy.

Glutamate facilitates the biosynthesis of glutathione, which can donatea reducing equivalent to unstable molecules such as reactive oxygenspecies (ROS) and free radicals. After reducing an oxidative species, itcan form a glutathione disulfide with another reactive glutathione,providing a mechanism of depleting oxidative stress inducing moleculesfrom cells (maintains high concentrations of up to 5 mM in the liver).Glutathione also is a cofactor for iNOS, allow maximal synthesis of NOin the arg-NO pathway.

Glutamate with co-agonists glycine or serine is an agonist of NMDAreceptors, releasing Ca2+ as a second messenger in many cellularsignaling pathways. There are dopaminergic and glutaminergicabnormalities implicated in schitzophrenia, with NMDA antagonistsmimicking some positive and negative symptoms of schitzophrenia, whilecarrying less risk of brain harm than do dopamine agonists. Ketamine andPCP, for example, produce similar phenotypes observed in schitzophrenia,with PCP showing less representative symptomology yet similar brainstructure changes. Glutamate receptors have increased function,contributing to the onset of schizophrenia. An increased proportion ofpost-synaptic glutamate receptors to pre-synaptic glutamate receptorsresult in increased glutamate signaling. Both agonizing and antagonizingNMDA receptors has shown some benefit in treating Alzheimer's dementia,depending on the MOA and receptor specificity. Thus delivering proteinswith either high or low levels of Glutamate, which also as NMDA agonistactivity, could be therapeutic for this patient population. Proteinswith low levels of Glutamate would likely provide a synergistic benefitalongside NMDA antagonists, such as Memantine. Likewise, clinical trialson LY2140023 have demonstrated Glutamate-based treatments as havingpotential for treating schizophrenia without the side effects seen withxenochemical anti-psychotics. Similar studies combining co-agonistGlycine with anti-psychotics, showed improved symptomology, suggestingthat delivering high doses of Aspartate, also a NMDA agonist, will yieldsimilar therapeutic benefits in this patient population.

Low Glutamate

Glutamate and acetyl-CoA are converted into N-acetylglutamate in themitochondria. This pushes the hepatic urea cycle towards the activestate, useful for ammonia detoxification. This means that dietarydelivery of nutrients with low doses of Glutamate may be useful in thecontext of kidney disease, where patients struggle to clear urea fromtheir circulation. Elimination of Glutamate to limit uremia from theavailable nitrogen sources, while being able to maintain a limitedprotein intake to prevent tissue catabolism, is a novel strategy againsta disruptive nutritional consequence of kidney disease.

Glutamine:

Glutamine oxidizes in enterocytes of the small intestine, leading tonitrogeneous products ornithine, citrulline, arginine, and alanine.

Citrulline is produced from Glutamine as a by-product of a reactioncatalyzed by the NOS family. Dietary supplement of citrulline is knownto reduce plasma levels of glucose, homocysteine, and asymmetricdimethylarginine, which are risk factors for metabolic syndrome.L-citrulline accelerates the removal of lactic acid from muscles, likelydue to the affects on vascular tone and endothelial function. Recentstudies have also shown that L-citrulline from watermelon juice providesgreater recovery from exercise, and less soreness the next day. It alsoappears that delivery of L-citrulline as a free from results in lessuptake into cells in vitro than in the context of watermelon juice(which contains high levels of L-citrulline). This suggests anopportunity to deliver peptide doses, which can traffic arginine intomuscle tissue for conversion into citrulline by eNOS at the endothelialmembrane for improved efficacy.

High Glutamine

Glutamine is a well studied secretagogue that can stimulate the systemicrelease of insulin from beta-cells, growth hormone, prolactin, glucagon,progesterone, and placental lactogen. It has also been shown to reducecirculating glucocorticoids and stress hormones. This biology has directimplications on both digestive biology and the absorption of nutrientspresent in the intestine, as well as affecting energy balance bytriggering satiety signals mediated by endocrine hormones. The abilityto modulate these hormones provides a therapeutic opportunity fordecreasing caloric intake in metabolic disorders such as obesity oralternatively triggering appetite in muscle wasting, sarcopenia, andcachexia, as well as by shifting insulin sensitivity in the onset ofdiabetes.

Dietary Glutamine supplementation up-regulates anti-oxidative genes andlowers expression of proinflammatory genes in the adipose and smallintestinal tissues.

Glutamine is an important signaling molecule for stimulating mTOR1phosphorylation in a cell-specific manner. This regulates cellularprotein turnover (autophagy) and integrates insulin-like growth signalsto protein synthesis initiation across tissues. This biology has beendirectly linked to biogenesis of lean tissue mass in skeletal muscle,metabolic shifts in disease states of obesity and insulin resistance,and aging.

Glutamine is an amino acid that is maintained at sufficient levels tosupport the anabolic effects of EAAs. Lysine, Methionine, Threonine.Tryptophan, Leucine, Isoleucine, and Valine have been shown unable tosupport increased protein synthesis and whole-body growth when added toa 12.7% crude protein diet, indicating a deficiency in the anabolicmediating non-essential amino acids, including Glutamine.

Glutamine is slowly cyclized to pyroglutamate. Glutamine is thepreferred source of fuel for rapidly dividing cells, includingenterocytes, lymphocytes, macrophages, and tumors. Supplementation withglutamine in the diet has significant demonstrated benefits in gutintegrity and immune function in surgery, critical illness, burn andinfection. A 12-day burn injury study of Glutamine supplementation (0.35g/kg) showed decreased intestinal permeability, lower endotoxin levels,and shorter length of hospital stay. It provided 8.8×decrease vs 5.5×decrease in Lactulose/mannitol ratio after 3 days and a 6-day reductionin hospital stay. 2 week Glutamine total parenteral nutrition (TPN)(0.23 g/kg) vs Glutamine-Free TPN study of malnourished patients waitingfor surgery showed increased gut permeability in Glutamine-Free group.It provided a 3.6× vs 0.81× increase in Lactulose/Mannitol ratio after 2weeks. These improvements point to an opportunity to deliver high levelsof Glutamine in the clinic to improve intestinal immunity and reducedbacteremia.

This also improves lymphocyte counts systemically and reduces infectiouscomplications during a hospital stay. A study of glutaminesupplementation (26 g/day until discharge) in patients with serious burninjury shows 3× more frequent positive blood culture in standard totalenteral nutrition (TEN) vs Glutamine-enriched, significantly reducingmortality rate. Additionally, Glutamine supplementation shows increasedlymphocyte count and function, increased HGH, reduced infectiouscomplications, reduced hospital stay, reduced morbidity, reducedmortality, and reduced gut permeability.

Intramuscular levels of Glutamine decrease under catabolic states suchas stress, burn, injury, and sepsis. This decrease causes an netnegative protein in lean tissue. Administration of Glutamine to theskeletal muscle has been shown to increase protein synthesis whileinhibiting breakdown in-vitro. Furthermore, dose dependence fromphysiological concentrations (1 mM Glutamine) up to 15-fold higherconcentrations has been observed in skeletal muscle. The effect wasfurther demonstrated in mucosal cells taken from the small intestine.

Branched chain amino acids are all metabolic substrates for glutaminesynthesis, providing a source of Glutamine in the fetus, enhancingplacental and fetal growth, suggesting a role for Glutamine in mediatingtheir effects on anabolism in mammals. Moreover, it has been shown thatGlutamine levels and timing of availability from the plasma affect thecellular uptake of Leucine, and the subsequent profile of mTORactivation. A buildup of intracellular Glutamine is used for uptake ofLeucine via the Glutamine/Leucine antiporter, SLC7A5. Administration ofglutamine at equal proportions to Leucine in-vitro causes a moresustained stimulation of protein synthesis via mTOR, whereas priming thecells with Glutamine prior to Leucine administration leads to a morerapid, yet transient mTOR activation (Nicklin, P. et. al. Cell 2009).

A lack of ATP-producing substrates, as occurs in a fasted state, canlead to autophagy and the turnover of intracellular protein in thelysosome to provide an energy source. Low levels of the glucogenic aminoacids, including glutamine can stimulate hepatic autophagy, leading todegradation of liver function.

Low Glutamine

mTOR is a central signaling pathway which can be hijacked for theproliferation of fast-growing cancer cells, as is evidence by oncogeniccells' preferential uptake of Glutamine.

Glycine:

A lack of ATP-producing substrates, as occurs in a fasted state, canlead to autophagy and the turnover of intracellular protein in thelysosome to provide an energy source. Low levels of the glucogenic aminoacids, including glycine can stimulate hepatic autophagy, leading todegradation of liver function.

Glycine facilitates the biosynthesis of glutathione, which can donate areducing equivalent to unstable molecules such as reactive oxygenspecies (ROS) and free radicals. After reducing an oxidative species, itcan form a glutathione disulfide with another reactive glutathione,providing a mechanism of depleting oxidative stress inducing moleculesfrom cells (maintains high concentrations of up to 5 mM in the liver).Glutathione also is a cofactor for iNOS, allow maximal synthesis of NOin the arg-NO pathway.

Histidine:

Histidine is an essential amino acid, and is a precursor for carnosine.Carnosine is an antioxidant and transition metal ion-sequestering agent.It acts as an anti-glycating agent by inhibiting the formation ofadvanced glycation end products (AGEs). AGEs are prevalent in diabeticvasculature and contribute to the development of atherosclerosis. Thepresence of AGEs in various cells types affect both the extracellularand intracellular structure and function. (Golden, A. et. al. AdvancedGlycosylation End Products. Circulation 2006). Also, the accumulation ofAGEs in the brain is a characteristic of aging and degeneration,particularly in Alzheimer's disease. AGE accumulation explains manyneuropathological and biochemical features of Alzheimer's disease suchas protein crosslinking, oxidative stress, and neuronal cell death.Because of its combination of antioxidant and antiglycating properties,carnosine is able to diminish cellular oxidative stress and inhibit theintracellular formation of reactive oxygen species and reactive nitrogenspecies.

Histidine has antioxidant, anti-inflammatory, and anti-secretoryproperties. Histidine's imidazole rings have the ability to scavengereactive oxygen species (ROS), which are made by cells during acuteinflammatory response. Histidine administration inhibits cytokine andgrowth factors involved in cell and tissue damage. Histidineadministration is instrumental in rheumatoid arthritis treatment, andadministering 4.5 g daily has been used to effectively treat patientswith severe rheumatoid arthritis. Rheumatoid arthritis patients havebeen found to have low serum histidine levels due to its very rapidremoval from the blood. Low plasma Histidine levels have also been foundin patients with chronic renal failure, obese women (where it also hadnegative impact on oxidative stress and inflammation), pediatricpatients with pneumonia, and asthma patients. Histidine supplementationhas been shown to diminish insulin resistance, reduce BMI and fat mass.Histidine suppresses inflammation and oxidative stress in obese subjectswith a metabolic syndrome. Lastly, as a precursor to histamine,histidine increases levels of histamine in the blood and in the brain.Low blood histamine is found in some manic, schizophrenic, high copperand hyperactive groups of psychiatric patients.

Posttranslational modification of proteins involved in transcriptionalregulation is a mechanisms used to regulate genes. This modification canalter protein functions in specific ways. One form of modification isprotein methylation, which is one of the most abundant proteinmodifications. Protein methylation carries important biologicalfunctions, including gene regulation and signal transduction. Histidineplays a role in protein modification, and ultimately gene regulation, inthat it accepts methyl group transferred from S-adenosylmethionine byprotein methyltransferases (Young-Ho Lee and Michael R. Stallcup, MolEndocrinol. 2009 April; 23(4): 425-433).

Histidine supplementation can be instrumental in the treatment ofmultiple diseases including: Alzheimer's disease, diabetes,atherosclerosis, metabolic syndrome in women, rheumatoid arthritis, andvarious psychiatric conditions (manic, schizophrenic, high copper, andhyperactive groups). Additionally, due to its role in proteinmodifications, Histidine provides an avenue to combat diseases resultingfrom gene deregulation, including cancer.

Low Histidine

There exists a mechanistic understanding of how uncharged tRNAallosterically activates GCN2, leading to downstream phosphorylation oftranscription factors related to lipogenesis and protein synthesis,along with many biosynthetic pathways in eukaryotes (SREBP-1c, elF2a,and GCN4p discussed below). Diets devoid of an essential amino acidremarkably trigger this signaling within minutes after diet introduction(Hao et. Al., science 2005). Signaling through SREBP-1c has been shownin vivo to have dramatic effects on mobilizing lipid stores byrepressing genes related to lipogenesis. SREBP-1c has been shown tospecifically act on hepatic lipid synthesis, and an ability to cause ahepatic steatosis phenotype as well as increase in visceral fat mass(Knebel B, et. Al. Liver-Specific Expression of Transcriptionally ActiveSREBP-c Is Associated with Fatty Liver and Increased Visceral Fat Mass.PLoS, 2012). An unbalanced diet lacking Histidine has been shown tosignal GCN2 for rats on a basal casein diet with 1-5.4% of an amino acidmixture supplemented lacking Histidine. Histidine deprivation, throughits action on GCN2, has an effect on SREBP-1c and decreased physiologicmeasures of liver weight (and fatty liver phenotype), adipose tissueweight, cholesterol/triglyceride content, and food intake. Drivingdecreased fat mass, while maintaining lean mass, provides a therapeuticopportunity in areas such as obesity, diabetes, and cardiovascularhealth.

Isoleucine:

Isoleucine is an EAA, and is also a BCAA. Isoleucine is used incombination with other BCAAs to improve the nutritional status ofpatients suffering from hepatic disease. BCAAs, including isoleucine,serve as fuel sources for skeletal muscle during periods of metabolicstress; promote protein synthesis, suppress protein catabolism, andserve as substrates for gluconeogenesis. BCAAs, and specificallyisoleucine, are catabolized in the skeletal muscle, and stimulate theproduction of L-alanine and L-glutamine.

BCAAs have been shown to have anabolic effects on protein metabolism byincreasing the rate of protein synthesis and decreasing the rate ofprotein degradation in resting human muscle. Additionally. BCAAs areshown to have anabolic effects in human muscle during post enduranceexercise recovery. These effects are mediated through thephosphorylation of mTOR and sequential activation of 70-kD S6 proteinkinase (p70-kD S6), and eukaryotic initiation factor 4E-bindingprotein 1. P70-kD S6 is known for its role in modulating cell-cycleprogression, cell size, and cell survival. P70-kD S6 activation inresponse to mitogen stimulation up-regulates ribosomal biosynthesis andenhances the translational capacity of the cell (W-L An, et al., Am JPathol. 2003 August; 163(2): 591-607; E. Blomstrand, et al., J. Nutr.January 2006 136: 269S-273S). Eukaryotic initiation factor 4E-bindingprotein 1 is a limiting component of the multi-subunit complex thatrecruits 40S ribosomal subunits to the 5′ end of mRNAs. Activation ofp70 S6 kinase, and subsequent phosphorylation of the ribosomal proteinS6, is associated with enhanced translation of specific mRNAs.

BCAAs given to subjects during and after one session of quadricepsmuscle resistance exercise show an increase in mTOR, p70 S6 kinase, andS6 phosphorylation was found in the recovery period after the exercise.However, there was no such effect of BCAAs on Akt or glycogen synthasekinase 3 (GSK-3). Exercise without BCAA intake leads to a partialphosphorylation of p70 S6 kinase without activating the enzyme, adecrease in Akt phosphorylation, and no change in GSK-3. BCAA infusionalso increases p70 S6 kinase phosphorylation in an Akt-independentmanner in resting subjects. This mTOR activity regulates cellularprotein turnover (autophagy) and integrates insulin-like growth signalsto protein synthesis initiation across tissues. This biology has beendirectly linked to biogenesis of lean tissue mass in skeletal muscle,metabolic shifts in disease states of obesity and insulin resistance,and aging.

Isoleucine supplementation can be used to improve athletic performanceand muscle formation, prevent muscle loss that accompanies aging, aidthose suffering from hepatic disease, support the growing bodies ofchildren, and improve the nutritive quality of foods given to thestarving populations. Additionally, as a precursor for L-alanine andL-glutamine, isoleucine mediates their significant metabolic signalingactivities.

Low Isoleucine

In states of obesity and diabetes, animals have been shown to exhibitreduced hepatic autophagy, leading to increased insulin resistance.Autophagy is important for maintenance of the ER and cellularhomeostasis, which when stressed can lead to impaired insulinsensitivity. High fat diet feeding in animal models stresses the ER,while leading to depressed hepatic autophagy through over-stimulation ofmTORC1, which reinforces the progression towards insulin sensitivityimpaired beta-cell function in diabetes. Reducing the level of systemicIsoleucine provides an opportunity to lower mTORC1 activity and restorehealthy levels of autophagy.

There exists a mechanistic understanding of how uncharged tRNAallosterically activates GCN2, leading to downstream phosphorylation oftranscription factors related to lipogenesis and protein synthesis,along with many biosynthetic pathways in eukaryotes (SREBP-1c, elF2a,and GCN4p discussed below). Diets devoid of any EAAs remarkably triggerthis signaling within minutes after diet introduction (Hao et. Al.,science 2005). Signaling through SREBP-c has been shown in vivo to havedramatic effects on mobilizing lipid stores by repressing genes relatedto lipogenesis. SREBP-1c has been shown to specifically act on hepaticlipid synthesis, and an ability to cause a hepatic steatosis phenotypeas well as increase in visceral fat mass (Knebel, B, et. Al.Liver-Specific Expression of Transcriptionally Active SREBP-c IsAssociated with Fatty Liver and Increased Visceral Fat Mass. PLoS,2012). Isoleucine deprivation, through its action on GCN2, has an effecton SREBP-1c and decreased physiologic measures of liver weight (andfatty liver phenotype), adipose tissue weight, cholesterol, triglyceridecontent, and food intake. Driving decreased fat mass, while maintaininglean mass, provides a therapeutic opportunity in areas such as obesity,diabetes, and cardiovascular health.

Leucine:

Leucine is an essential amino acid and a branched chain amino acid. Thebranched chain amino acids, including Leucine, serve as fuel sources forskeletal muscle during periods of metabolic stress; promote proteinsynthesis, suppress protein catabolism, and serve as substrates forgluconeogenesis. BCAAs, and including Leucine, are catabolized in theskeletal muscle, and stimulate the production of L-alanine andL-glutamine. Leucine plays a direct role in the regulation of proteinturnover through cellular mTOR signaling and gene expression as well asserving to activate glumatate dehydrogenase.

BCAAs have been shown to have anabolic effects on protein metabolism byincreasing the rate of protein synthesis and decreasing the rate ofprotein degradation in resting human muscle. Additionally, BCAAs areshown to have anabolic affects in human muscle during post enduranceexercise recovery. These affects are mediated through thephosphorylation of mTOR and sequential activation of 70-kD S6 proteinkinase (p70-kD S6), and eukaryotic initiation factor 4E-bindingprotein 1. P70-kD S6 is known for its role in modulating cell-cycleprogression, cell size, and cell survival. P70-kD S6 activation inresponse to mitogen stimulation up-regulates ribosomal biosynthesis andenhances the translational capacity of the cell (W-L An, et al., Am JPathol. 2003 August; 163(2): 591-607; E. Blomstrand, et al., J. Nutr.January 2006 136: 269S-273S). Eukaryotic initiation factor 4E-bindingprotein 1 is a limiting component of the multi-subunit complex thatrecruits 40S ribosomal subunits to the 5′ end of mRNAs. Activation ofp70 S6 kinase, and subsequent phosphorylation of the ribosomal proteinS6, is associated with enhanced translation of specific mRNAs.

BCAAs given to subjects during and after one session of quadricepsmuscle resistance exercise show an increase in mTOR, p70 S6 kinase, andS6 phosphorylation was found in the recovery period after the exercise.However, there was no such effect of BCAAs on Akt or glycogen synthasekinase 3 (GSK-3). Exercise without BCAA intake leads to a partialphosphorylation of p70 S6 kinase without activating the enzyme, adecrease in Akt phosphorylation, and no change in GSK-3. BCAA infusionalso increases p70 S6 kinase phosphorylation in an Akt-independentmanner in resting subjects. Leucine is furthermore known to be theprimary signaling molecule for stimulating mTOR1 phosphorylation in acell-specific manner. This regulates cellular protein turnover(autophagy) and integrates insulin-like growth signals to proteinsynthesis initiation across tissues. This biology has been directlylinked to biogenesis of lean tissue mass in skeletal muscle, metabolicshifts in disease states of obesity and insulin resistance, and aging.

Leucine is a well-studied secretagogue that can stimulate the systemicrelease of insulin from beta-cells, growth hormone, prolactin, glucagon,progesterone, and placental lactogen. This biology has directimplications on both digestive biology and the absorption of nutrientspresent in the intestine, as well as affecting energy balance bytriggering satiety signals mediated by endocrine hormones. The abilityto modulate these hormones provides a therapeutic opportunity fordecreasing caloric intake in metabolic disorders such as obesity oralternatively triggering appetite in muscle wasting, sarcopenia, andcachexia, as well as by shifting insulin sensitivity in the onset ofdiabetes.

Leucine activates glutamate dehydrogenase, which is an enzyme thatcatalyzes the reversible interconversion between glutamate,a-ketoglutarate, and ammonia. In mammals, glutamate dehydrogenase hashigh levels of activity in the liver, kidney, brain, and pancreas. Inthe liver, glutamate dehydrogenase provides the appropriate ratio ofammonia and amino acids for urea synthesis in periportal hepatocytes,and the glutamate dehydrogenase reactions seem to be in aclose-to-equilibrium state. Additionally, glutamate dehydrogenase hasbeen shown to produce glutamate for glutamine synthesis in a small rimof pericentral hepatocytes, enabling it to serve as either a source forammonia or an ammonia scavenger. In the kidney, glutamate dehydrogenasefunctions to produce ammonia from glutamate to control acidosis (C.Spanaki and A. Plaitakis, Neurotox Res. 2012 January; 21(1):117-27).

Leucine supplementation can be used to improve athletic performance andmuscle formation, prevent muscle loss that accompanies aging, aid thosesuffering from hepatic disease, support the growing bodies of children,and improve the nutritive quality of foods given to the starvingpopulations. Additionally, leucine plays an important role in ureasynthesis in hepatocytes, and may be given to treat those who sufferfrom conditions that cause them to be hyperammonemic. Lastly, leucinemay be used to treat acidosis.

Low Leucine

In states of obesity and diabetes, animals have been shown to exhibitreduced hepatic autophagy, leading to increased insulin resistance.Autophagy is important for maintenance of the ER and cellularhomeostasis, which when stressed can lead to impaired insulinsensitivity. High fat diet feeding in animal models stresses the ER,while leading to depressed hepatic autophagy through over-stimulation ofmTORC1, which reinforces the progression towards insulin sensitivityimpaired beta cell function in diabetes. Reducing the level of systemicLeucine provides an opportunity to lower mTORC1 activity and restorehealthy levels of autophagy.

mTOR is a central signaling pathway which can be hijacked for theproliferation of fast-growing cancer cells. Depletion of Leucine mayreduce a fast-growing cell's ability to sustain constitutive mTORactivation.

There exists a mechanistic understanding of how uncharged tRNAallosterically activates GCN2, leading to downstream phosphorylation oftranscription factors related to lipogenesis and protein synthesis,along with many biosynthetic pathways in eukaryotes (SREBP-1c, eIF2a,and GCN4p discussed below). Diets devoid of an EAA remarkably triggerthis signaling within minutes after diet introduction (Hao et. Al.,science 2005). Signaling through SREBP-1c has been shown in vivo to havedramatic effects on mobilizing lipid stores by repressing genes relatedto lipogenesis. SREBP-1c has been shown to specifically act on hepaticlipid synthesis, and an ability to cause a hepatic steatosis phenotypeas well as increase in visceral fat mass (Knebel, B, et. Al.Liver-Specific Expression of Transcriptionally Active SREBP-1c IsAssociated with Fatty Liver and Increased Visceral Fat Mass. PLoS,2012). Leucine deprivation, through its action on GCN2, has an affect onSREBP-1c and decreased physiologic measures of liver weight (and fattyliver phenotype), adipose tissue weight, cholesterol/triglyceridecontent, and food intake. Driving decreased fat mass, while maintaininglean mass, provides a therapeutic opportunity in areas such as obesity,diabetes, and cardiovascular health.

Leucine deprivation, furthermore, has directly shown up-regulation ofUCP1 in brown adipose tissue (BAT), a direct measure of thermogenesis,an increase in energy expenditure (presumably due to an increase inthermogenesis in BAT), and a corresponding decrease in fat mass bystimulation of lipolysis in the white adipose tissue (WAT). UCP1up-regulation results in decreased food intake, body weight, abdominalfat mass, fat mass, and maintenance of lean mass (Guo, F. The GCN2elF2alpha kinase regulates fatty-acid homeostasis in the liver duringdeprivation of an essential amino acid. Cell Metab., 2007).

Lysine:

Lysine is an EAA that is important for proper growth, and plays a vitalrole in the production of carnitine. Camitine is a quaternary amine thatplays an important role in the production of energy in the myocardium.Carnitine transports free fatty acids into the mitochondria, and in sodoing, increases the preferred substrate for oxidative metabolism in theheart. Additionally, carnitine prevents the fatty acid accumulation thatoccurs during ischemic events, which may lead to ventriculararrhythmias. As the myocardial carnitine levels are quickly diminishedduring an ischemic event, exogenous supplementation with carnitinereplenishes the depleted myocardial carnitine levels and improve cardiacmetabolic and left ventricular function. Additionally, an analysis of 4studies demonstrated that supplementation with L-carnitine after anacute myocardial infarction (AMI), in comparison to a placebo,significantly reduces left ventricular dilation in the first year afterthe AMI. This is significant because the prevention of left ventriculardilation and the preservation of cardiac function after an AMI is apowerful predictor of the progression to heart failure and death.Additionally, carnitine aids in lowering cholesterol, which furthersupports heart health, and aids in the prevention of acute myocardialinfarctions (James J. DiNicolantonio, et al., Mayo Clinic Proceedings.2013: 88, 544-551).

Lysine supplementation is useful to support heart health and duringischemic events to prevent ventricular arrhythmia. In addition, Lysinesupplementation may help heart attack patients recover effectively, andaid in the prevention of heart attacks in those with the leftventricular dilation. Also, Lysine can be used for to decreasecholesterol levels in patients with high cholesterol.

Lysine is instrumental in helping the body to absorb calcium anddecreases the amount of calcium that is lost in urine. Due to calcium'srole in bone health, Lysine supplementation is helpful in preventing thebone loss that is associated with osteoporosis. Furthermore, acombination of L-arginine and Lysine makes the bone building cells moreactive and enhances production of collagen, which is substance that isimportant for bones and connective tissues including: skin, tendon, andcartilage.

Lysine supplementation is useful for patients suffering fromosteoporosis, and those at risk for developing osteoporosis; theelderly, menopausal women, growing children, in cosmetics due to itsrole in collagen production, and athletes for improved ligamentintegrity.

A lysine deficiency causes fatigue, nausea, dizziness, loss of appetite,agitation, bloodshot eyes, slow growth, anemia, and reproductivedisorders.

Lysine helps to prevent and suppress outbreaks of cold sores and genitalherpes when taken on a regular basis. When 45 patients with frequentlyrecurring herpes infection were given 312-1200 mg of lysine daily insingle or multiple doses, recovery from the infection and suppression ofrecurrence was evidenced (Griffith R. S., et al., Dermatologica1978:156:257-267). This is because lysine has antiviral effects, whichact by blocking the activity of arginine, which promotes herpes simplexvirus (HSV) replication. In tissue culture studies, herpes viralreplication is enhanced when the arginine/lysine ratio favors arginine.However, when the arginine/lysine ratio favors lysine, viral replicationis suppressed, ad cyto-pathogenicity of HSV is inhibited. (Griffith R.S. et al., Dermatologica 1978; 156:257-267). It has been shown that orallysine is more effective for preventing an outbreak than it is atreducing the severity and duration of the outbreak.

Supplementing the diet with Lysine for those infected with the HSVsuppresses outbreak of cold sores and genital warts, and when activelytaken on a regular basis is very beneficial in the prevention ofoutbreaks.

Lysine modulates the arginine-NO pathway. NO is important for normalendothelial function and cardiovascular health (including vascular tone,hemodynamics, angiogenesis). Lysine is a natural inhibitor of L-argininetransport, and competes with L-arginine for uptake through the systemy+, which is the major transport system of cationic amino acids inmammalian cells. Excess nitric oxide contributes to refractoryhypotension associated with sepsis, and can be combatted withadministration of L-lysine because it inhibits Arginine, which is animportant component of NO synthesis (K. G. Allman, et al., BritishJournal of Anaesthesia (1998) 81: 188-192). Moreover, an excess of NOmay lead to diseases, due to its release from cerebral vasculature,brain tissue, and nerve endings, which are prime regions forneurodegeneration. Excess NO may lead to migraines, brain cell damagethat can lead to neurodegenerative diseases like Parkinson disease,Alzheimer's disease, Huntington disease, and amyotrophic lateralsclerosis. Furthermore, NO that is produced by the pancreas may damagethe beta-cells as occurs in type 1 diabetes.

Lysine supplementation is useful for the prevention of hypotensionassociated with sepsis by preventing vasodilation. Additionally, lysinemay be used to prevent/treat migraines, and prevent/slow down theprogression of neurodegenerative diseases like AD, Parkinson's disease,Huntington, and amyotrophic lateral sceloris.

Low Lysine

There exists a mechanistic understanding of how uncharged tRNAallosterically activates GCN2, leading to downstream phosphorylation oftranscription factors related to lipogenesis and protein synthesis,along with many biosynthetic pathways in eukaryotes (SREBP-1c, eIF2a,and GCN4p discussed below). Diets devoid of an EAA remarkably triggerthis signaling within minutes after diet introduction (Hao et. Al.,science 2005). Signaling through SREBP-1c has been shown in vivo to havedramatic effects on mobilizing lipid stores by repressing genes relatedto lipogenesis. SREBP-1c has been shown to specifically act on hepaticlipid synthesis, with an ability to cause a hepatic steatosis phenotypeas well as increase in visceral fat mass (Knebel, B, et. Al.Liver-Specific Expression of Transcriptionally Active SREBP-1c IsAssociated with Fatty Liver and Increased Visceral Fat Mass. PLoS,2012). Lysine deprivation, through its action on GCN2, has an affect onSREBP-1c and decreased physiologic measures of liver weight (and fattyliver phenotype), adipose tissue weight, cholesterol/triglyceridecontent, and food intake. Driving decreased fat mass, while maintaininglean mass, provides a therapeutic opportunity in areas such as obesity,diabetes, and cardiovascular health.

Methionine:

Methionine is an essential amino acid, and is the initiating amino acidin the synthesis of virtually all eukaryotic proteins. Methionine is oneof the most hydrophobic AAs. Most of the methionine residues in globularproteins can be found in the interior of the hydrophobic core.Methionine is often found to interact with the lipid bilayer inmembrane-spanning protein domains. Due to its location and powerfulantioxidative properties, methionine has been regarded as endogenousantioxidants in proteins (John T. Brosnan and Margaret E. Brosnan, J.Nutr. June 2006 vol. 136 no. 6 1636S-1640S). Methionine residues have ahigh susceptibility to oxidation by oxidases, ozone, hydrogen peroxide,superoxide, γ-irradiation, metal-catalyzed oxidation, “leakage” from theelectron transport chain, and auto-oxidation of flavins or xenobiotics.Once oxidized, the Methionine residue is converted to methioninesulfoxide, which can be converted back to Methionine though methioninesulfoxide reductases (Rodney L. Levine, et al., Proc Natl Acad Sci USA,1996 Dec. 24; 93(26): 15036-15040). As an antioxidant, methioninesupplementation can aid in the prevention of cancer, degenerativediseases, heart disease, liver and kidney pathologies. It can also beused in cosmetics to fight the damage of UV rays to the skin.

Methionine is a lipotropic AA, and helps the liver process lipids, andthereby helps prevent the build-up of fat in the liver and arteries thatmay ultimately lead to an obstruction of blood flow to the brain, heart,and kidneys. Additionally, the build-up of fat in the liver drives apathology known as hepatic steatosis, which may ultimately lead tocirrhosis of the liver. Methionine supplementation for individualsundergoing drug detoxification may improve the process, as well as forthose taking medications which have toxic side effects.

In addition, to being a lipotropic AA, Methionine promotes heart healthby increasing of the liver's production of lectithin, which is known tohelp reduce cholesterol levels. Methionine supplementation can preventcirrhosis of the liver from fat deposition therein. Additionally, it canpromote cardiovascular health by preventing the deposition of fat intothe arteries, thereby preventing possible myocardial infarctions andstrokes. Further, Methionine may help those with high cholesterol levelslower their cholesterol improving the risk of cardiovascular disease

Methionine aids in the proper functioning of the immune system in thatelevated levels of methionine increases the levels of taurine, andhomocysteine and glutathione which help improve immune function. Theunderlying mechanism for the immune functions may involve mTORactivation, NO and glutathionine synthesis, H2S signaling, and cellularredox state. Methionine is a precursor for Taurine, which modulates thearginine-NO pathway. NO is important for normal endothelial function andcardiovascular health (including vascular tone, hemodynamics,angiogenesis).

Methionine is also converted into cysteine, which is a precursor forGlutathionine. Glutathionine is a powerful neutralizer of toxins in theliver, and helps to protect the liver from the damaging effects oftoxins. Additionally, this detoxifying ability helps to diminish muscleweakness, prevents brittle hair, and protects against radiationassociated with these toxins. As a result, it is beneficial for thosesuffering from chemical allergies or exposure to high levels of airpollution. Methionine can be helpful to patients with compromised immunesystems, such as AIDS patients and cancer patients. Likewise, it can bea useful supplement during flu seasons, particularly to groups who aremost susceptible, including: the elderly, children, and pregnant women.Furthermore, it can be used for those travelling to countries where theywill likely be susceptible to regional infections. Methionine levels areobserved to be lower in patients with AIDS. This decreased level ofmethionine has been linked to deterioration in the nervous system thatleads to symptoms like dementia, and diminished memory recall.Supplementing with 6 grams of methionine per day can lead toimprovements in the memory recall in these patients. Likewise,Methionine can be beneficial to those who have diseases that involvenervous system degeneration including Alzheimer's Disease, ALS, MS, andHuntington's.

Methionine participates in one-carbon metabolism, and thereby alsoparticipates in the methylation of proteins and DNA, which in turn helpsregulate gene expression and the biological activity of proteins.Methionine supplementation for those at risk for related geneticdisorders can be used to promote proper gene regulation in allindividuals.

Low Methionine

Methionine is a precursor for the toxic homocysteine, which mediatesADMA by down-regulating DDAH in body to metabolize ADMA, interferingwith the arginine-NO pathway. NO is important for normal endothelialfunction and cardiovascular health (including vascular tone,hemodynamics, angiogenesis).

There exists a mechanistic understanding of how uncharged tRNAallosterically activates GCN2, leading to downstream phosphorylation oftranscription factors related to lipogenesis, protein synthesis, alongwith many biosynthetic pathways in eukaryotes (SREBP-1c, eIF2a, andGCN4p discussed below). Diets devoid of any EEAs remarkably trigger thissignaling within minutes after diet introduction (Hao et. Al., science2005). Signaling through SREBP-1c has been shown in vivo to havedramatic effects on mobilizing lipid stores by repressing genes relatedto lipogenesis. SREBP-1c has been shown to specifically act on hepaticlipid synthesis, and an ability to cause a hepatic steatosis phenotypeas well as increase in visceral fat mass (Knebel, B. et. Al.Liver-Specific Expression of Transcriptionally Active SREBP-1c IsAssociated with Fatty Liver and Increased Visceral Fat Mass. PLoS,2012). Methionine deprivation, through its action on GCN2, has an affecton SREBP-1c and decreased physiologic measures of liver weight (andfatty liver phenotype), adipose tissue weight, cholesterol/triglyceridecontent, and food intake. Driving decreased fat mass, while maintaininglean mass, provides a therapeutic opportunity in areas such as obesity,diabetes, and cardiovascular health.

Phenylalanine:

Phenylalanine is an EEA, AuAA, and precursor for synthesis ofnorepinephrine in the brain, as well as a metabolic precursor fortyrosine, which is another aromatic amino acid and precursor for thesynthesis of dopamine.

Norepinephrine (NE) is synthesized in the adrenal medulla andpostganglionic neurons in the sympathetic nervous system by theβ-oxidation of dopamine by β-hydroxylase along with the cofactorascorbate. It works by being secreted into the synaptic cleft where itstimulates adrenergic receptors and is then either degraded or up-takenby surrounding cells. As a cathecolamine, it does not cross theblood-brain barrier.

NE can be used to combat attention-deficit/hyperactivity disorders(ADHD), depression, and hypotension. In terms of attention disorders,like ADHD, medications prescribed tend to help increase levels of NE anddopamine. Furthermore, depression is typically treated with medicationsthat inhibit the reuptake of serotonin and NE thereby increasing theamount of serotonin and NE that is available in the postsynaptic cellsin the brain. Recent evidence has suggested thatserotonin-norepinephrine reuptake inhibitors (SNRIs) may also increasedopamine transmission because if the norepinephrine transporterordinarily recycled dopamine as well then SNRIs will also enhance thedopaminergic transmission. As a result, the effects antidepressants mayalso be associated with the increased NE levels may partly be due to thesimultaneous increase in dopamine (in particular in the prefrontalcortex of the brain).

NE is used to treat patients with critical hypotension. NE is avasopressor and acts on both α1 and α2 adrenergic receptors to causevasoconstriction, thereby increasing the blood pressure.

As a precursor for NE, Phenylalanine can be used to treat attentiondisorders like ADHD and ADD. Additionally, it can be used to treat thosesuffering from depression or post-traumatic stress syndrome.Phenylalaline can also be used to treat depression or alter the functionof neurotransmitter modulating drugs such as SSRIs. Additionally, due toits ability to increase blood pressure through the increase of vasculartone, it may be used to treat those with a hypotensive tendency.Furthermore, phenylalanine may be used as an upstream regulator oftyrosine levels, and thereby Tyrosine function.

Tyrosine supplementation can help in the treatment of Parkinson'sdisease due to its role as a precursor to L-DOPA and dopamine.Additionally, it can be used in the treatment of those withemotional/psychiatric disorder like depression and in the treatment ofaddiction. Furthermore, it can promote learning by increasing thereward/pleasure response during learning difficult or complex conceptsor movements.

Dopamine, which is a monoamine catecholamine neurotransmitter, plays aregulatory role in the immune system. Neurotransmitters andneuropeptides that interact with specific receptors present inparticular immune effector cells are released by the immune system toinfluence the functions of these cells in the host against disease andother environmental stress. The immunoregulatory actions of dopaminehave been shown to be regulated via five different G protein-coupledreceptors that are present in target cells. There are two broad classesof these receptors: G1 and G2, which encompass the varying subtypes. TheD1 class of receptors includes D2 and D5 subtypes, and increaseintracellular cAMP upon activation. The D2 class of receptors consistsof the D2, D3, and D4 subtypes, and has been reported to inhibitintracellular cAMP upon stimulation. Dopamine receptors have been foundon normal human leukocytes. Likewise, the lymphoid tissues havedopaminergic innervations through sympathetic nerves, which suggeststhat dopamine may be able to regulate the immune system effector cells(Basu, Sujit & Sarkar, Chandrani. Dopamine and immune system. SciTopics2010).

Dopamine affects T cells by activating the resting T cells andinhibiting the activation of stimulated T cells. In normal restingperipheral human T lymphocytes, dopamine activates the D2 and D3subclass of receptors, which in turn activates integrins (α4β1 andα5β1). These integrins are hetrodimeric transmembrane glycoproteins thatattach cells to the extracellular matrix component, fibronectin.Fibronectin is used for the trafficking and extravasation of T cellsacross the tissue barriers and blood vessels. Furthermore, dopamine actsthrough the D3 receptors to selectively induce the migration and homingof CD8+ T cells. Moreover, dopamine affects T cells by influencing thesecretions of cytokines by the T cells. When dopamine stimulates the D3and D1/D5 receptors, the secretion of TNF-α (a pleiotropic inflammatorycytokine) is increased. When the D2 receptors are stimulated, IL-10 (ananti-inflammatory cytokine) is induced to secrete. Dopamine, however,can inhibit the activated T cell receptor induced cell proliferation andsecretion of a number of cytokines like 11-2, IFN-γ and IL-4 through thedown-regulation of the expression of non-receptor tyrosine kinases Ickand fyn, which are important tyrosine kinases in the initiation of TCRactivation (Basu. Sujit & Sarkar. Chandrani Dopamine and immune system.SciTopics 2010).

The B cells have a very high expression of dopamine D2, D3, and D5receptors. Dopamine has the ability to inhibit the proliferation of theresting and the malignant B lymphocytes. Dopamine acts by promotingapoptosis in cycling B cells through oxidative stress. However, thisdopaminergic action has not been observed in resting lymphocytes,therefore suggesting a role in the prevention of cancer (Basu. Sujit &Sarkar, Chandrani, Dopamine and immune system. SciTopics 2010).

Tyrosine, as a precursor for Dopamine, can be used to improve immuneresponses and improve the overall immune system functionality. It canprovide a benefit to the elderly, women who are pregnant, children, andthose with compromised immune functions like AIDS patients, and cancerpatients. It also can be given to teachers, those travelling, and anyonefrequently exposed to germs.

Epinephrine, which is popularly known as adrenaline, is a hormone thatis secreted by the medulla of the adrenal glands. Epinephrine isreleased in response to strong emotions such as fear or anger, whichcauses an increase in heart rate, muscle strength, blood pressure, andsugar metabolism. It is responsible for the flight or fight responsethat prepares the body for difficult or strenuous activity. Epinephrineis used as a stimulant during cardiac arrest, as a vasoconstrictorduring shock to increase blood pressure, and as a bronchodilator andantispasmodic in bronchial asthma. Epinephrine is not found in largequantities in the body, but is nevertheless very important in themaintenance of cardiovascular homeostasis because it has the ability todivert blood to tissues under stress. Epinephrine has this effect byinfluencing muscle contraction. Contraction of the muscles occursthrough the binding calmodulin to calcium ions when the concentration is10×larger than normal in the cell. The calcium-calmodulin complex thengoes on to activate the myosin light chain kinase, which thenphosphorylates the LC2 causing the contraction. Epinephrine binds to theepinephrine receptors, which activates adenylyl cyclase, and producescyclic AMP from ATP, cAMP activates a protein kinase which thusphosphorylates the myosin light chain kinase. This phosphorylated myosinlight chain kinase has a lower affinity for the calcium-calmodulincomplex, and is thus inactive. As such, the smooth muscle tissue isrelaxed. It is this action of epinephrine that makes it very useful intreating asthma, cardiac arrest, and anaphylactic shock. Tyrosine, as aprecursor for Epinephrine, can be used for patients who are at risk forcardiac arrest, those suffering from asthma, and those who are at riskfor anaphylactic shock.

Epinephrine is one of two main hormones that breakdown glycogen bybinding to a receptor on exterior of a liver cell. This binding causes aconformational change to take place thereby allowing G protein to bindand become active. The activation of the G-protein coupled receptorcauses a conformational change on the molecule to occur which causesadenylate cyclase to bind. Onceadenylate cyclase binds the complex,adenylate cyclase breaks down ATP into cAMP, which then becomes thesecond messenger protein in this process and activates protein kinase.The activated protein kinase activates phosphorylase, which is an enzymethat catalyzes breaks down the glycogen to glucose. Tyrosine, as aprecursor for Epinephrine, can be used to improve athletic performanceby making glucose readily available to fuel exercise.

Melanin is a metabolite of Tyrosine, and is a powerful antioxidant.Additionally, it is influential in the inhibition of the production ofinflammatory cytokines and superoxide. When pro-inflammatory cytokinesare overproduced, it mediates the damaging effects of inflammation inpathologic conditions like rheumatoid arthritis, graft vs. hostreactions, cachexia, and sepsis syndrome. It has been found that melanininhibits ongoing cytokine synthesis, which strongly suggests thatmelanin may be useful as a superimposed therapy for conditions thatinvolve proinflammatory cytokines (Mohagheghpour N., et al., CellImmunol. 2000 Jan. 10; 199(1):25-36).

Tyrosine can be used in the treatment of rheumatoid arthritis, cachexia,sepsis syndrome, those with inflammation related to autoimmune disorder,and other inflammatory sequela of pathologic conditions.

Phenylalanine up-regulates the activity of GTP cyclohydrolase-I, freeingtetrahydrobiopterin (THB) for NO synthesis and the hydroxylation ofArAAs by aromatic amino acid hydroxylase (AAAH). For this reason,delivery of high levels of Phenylalanine to raise cellular levels of THBdirectly stimulates the biosynthesis of many neurotransmitters in theCNS capillary endothelial cells. ArAAs serve as precursors forbiosynthesis of monoamine neurotransmitters, including melatonin,dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline).In promoting NO synthesis, phenylalanine can be used to treathypertension, to decrease blood pressure, and may be used in the contextof diving, or those travelling to high altitudes to increasevasodilation.

Low Phenylalanine

There exists a mechanistic understanding of how uncharged tRNAallosterically activates GCN2, leading to downstream phosphorylation oftranscription factors related to lipogenesis and protein synthesis,along with many biosynthetic pathways in eukaryotes (SREBP-1c, eIF2a,and GCN4p discussed below). Diets devoid of any EAAs remarkably triggerthis signaling within minutes after diet introduction (Hao et. Al.,science 2005). Signaling through SREBP-1c has been shown in vivo to havedramatic effects on mobilizing lipid stores by repressing genes relatedto lipogenesis. SREBP-1c has been shown to specifically act on hepaticlipid synthesis, and an ability to cause a hepatic steatosis phenotypeas well as increase in visceral fat mass (Knebel, B. et. Al.Liver-Specific Expression of Transcriptionally Active SREBP-1c IsAssociated with Fatty Liver and Increased Visceral Fat Mass. PLoS,2012). Phenylalanine deprivation, through its action on GCN2, has aneffect on SREBP-1c and decreased physiologic measures of liver weight(and fatty liver phenotype), adipose tissue weight, cholesterol,triglyceride content, and food intake. Driving decreased fat mass, whilemaintaining lean mass, provides a therapeutic opportunity in areas suchas obesity, diabetes, and cardiovascular health.

Proline:

Citrulline is produced from Glutamine as a by-product of a reactioncatalyzed by the NOS family. Dietary supplement of citrulline is knownto reduce plasma levels of glucose, homocysteine, and asymmetricdimethylarginine, which are risk factors for metabolic syndrome.L-citrulline accelerates the removal of lactic acid from muscles, likelydue to the effects on vascular tone and endothelial function. Recentstudies have also shown that L-citrulline from watermelon juice providesgreater recovery from exercise and less soreness the next day. It alsoappears that delivery of L-citrulline as a free form results in lessuptake into cells in vitro than in the context of watermelon juice(which contains high levels of L-citrulline). This suggests anopportunity to deliver peptide doses, which can traffic arginine intomuscle tissue for conversion into citrulline by eNOS at the endothelialmembrane for improved efficacy.

Changes in NO synthesis and polyamines (via Proline), are seen duringgestation when placental growth rate peaks, indicating a role forarginine in fetal development during pregnancy.

Serine:

Serine is a nonessential amino acid, and is biosynthesized fromglycolysis via 3-phosphoglycerate. Serine plays a vital role inintermediary metabolism in that it contributes to phospholipid,sphingolipid, and cysteine biosynthesisas well as tryptophan synthesisin bacteria and is a primary source of glycine. The body has a need forglycine, which probably exceeds dietary intake by 10-50 fold. Thisdemand is not only for the synthesis of protein, particularly collagen,but also for glycine being a precursor for 5 major metabolicbiosynthetic pathways: creatine, porphyrins, purines, bile acids, andglutathione. Additionally, due to its role in glycine production, serineis also a major donor of folate-linked one-carbon units that are used inthe biosynthesis of purines and 2′ deoxythymidine 5′-monophosphate andthe remethylation of homocystein to methionine. It is important to notethat for every glycine molecule that is derived from serine, there isone-carbon unit formed. (Cook, R. Defining the steps of the folateone-carbon shuffle and homocysteine metabolism 1′2; Am. J Clin Nutr;2000)

In one-carbon metabolism, one-carbon units for biosynthesis are carriedand chemically activated by a family of cofactors calledtetrahydrofolate (THF) polyglutamates. THF-mediated one-carbonmetabolism is a metabolic system of interdependent biosynthetic pathwayscompartmentalized in the cytoplasm, the mitochondria, and the nucleus.In the cytoplasm, one-carbon metabolism is used for the synthesis ofpurines and thymidylates and the remethylation of homocysteine tomethionine (an overabundance of homocysteine may be harmful to thebody). In the mitochondria, one-carbon metabolism is used for thesynthesis of formylated methionyl-tRNA; the catabolism of choline,purines, and histidine; and the interconversion of serine and glycine.Additionally, the mitochondria is the primary source for one-carbonunits for cytoplasmic metabolism. Disruption of the folate-mediatedone-carbon metabolism has been linked with many pathologies anddevelopmental anomalies. (J. T. Fox and P. J. Stover, Chapter i,Folate-Mediated One-Carbon Metabolism, In: Gerald Litwack, Editor(s),Vitamins & Hormones, Academic Press, 2008, Volume 79, Pages 1-44).

Serine hydroxymethyltransferase (SHMT) catalyzes the freely reversibleinterconversion of serine and glycine in a reaction that is both folate-and pyridoxal 5-phosphate dependent. The conversion of serine to glycineinvolves the removal of the C-3 serine and the formation of5,10-methylenetetrahydrofolate, which can be utilized in thefolate-dependent one-carbon metabolism or oxidized to carbon dioxide via10-foryltetrahydrofolate (Robert J Cook, Am J Clin Nutr December 2000vol. 72 no. 6 1419-1420).

Serine is a precursor for cysteine. Cysteine is synthesized fromhomocysteine, which is itself synthesized from the metabolism ofmethionine. Serine is involved in cysteine's synthesis by condensingwith homocysteine to form cystathionine. Cystathionine is thendeaminated and hydrolyzed to form cysteine and alpha ketobutyrate.Cysteine's sulfur comes from homocysteine, but the rest of the moleculecomes from the initial serine residue. The biosynthesis of cysteineoccurs via a different mechanism in plants and prokaryotes. Cysteine isa vital amino acid because it plays an important role in proteinfolding. The disulfide linkages formed between cysteine residues helpsto stabilize the tertiary and quaternary structure of proteins, andthese disulfide linkages are most common among the secreted proteins,where proteins are exposed to more oxidizing conditions that are foundin the cellular interior. Despite the benefits of homocysteine, highlevels can be a risk factor for developing cardiovascular disease.Elevated homocysteine may be caused by a genetic deficiency ofcystathionine beta-synthase and excess methionine intake may be anotherexplanation. Control of methionine intake and supplementing with folicacid and vitamin B12 in the diet have been used to lower homocysteinelevels. Likewise, increased Serine levels to support homocysteine tocysteine conversion can be beneficial.

N-methyl-D-aspartate (NMDA) is one of the most fundamentalneurotransmitters in the brain. It is a glutamate receptor and is avital molecular device for the control of synaptic plasticity and memoryfunction. This receptor is an ionotropic receptor for glutamate and ischaracterized by high affinity for glutamate, a high unitaryconductance, high calcium permeability, and a voltage-dependent block bymagnesium ions. In order for the NMDA receptor to open, it is bound byglutamate and glycine or D-serine. D-serine is a neurotransmitter and agliotransmitter that is biosynthesized in the brain by serine racemasefrom L-serine. It is a powerful or potent agonist to glycine for theNMDA receptor binding site. (Jean-Pierre Mothet, et al., Proc Natl AcadSci USA, 2000, 97 (9) 4926-4931; Zito K and Scheuss V. (2009) NMDAReceptor Function and Physiological Modulation. In: Encyclopedia ofNeuroscience (Squire L R, ed), volume 6, pp. 1157-1164. Oxford: AcademicPress).

Serine plays an important role in learning and synaptic plasticity, as aresult, serine supplementation can be useful to the elderly, growingchildren, school age children, and those experiencing learningdifficulties. Additionally, it can be given to anyone trying to learn anew task, be it an instrument, or athletes/dancers trying to improve orlearn new exercises and movements. Furthermore, due to its role as aprecursor for cysteine, may be given as an upstream regulator for theeffects of cysteine. As a precursor for the synthesis of glycine, serinemay be used in cosmetic products, to combat aging, and promote propergrowth because of its role in collagen synthesis. Furthermore, it can beused to improve athletic abilities because of its role in the creatinebiosynthetic pathway. Moreover, it may be very useful in thedetoxification and immune health because of its role in theglutathionine metabolic pathway.

Threonine:

Threonine is an EAA, and is one of the few AAs that is not convertedinto its L-isomer via transaminases and d-AA oxidases. Threonine is usedfor the synthesis of mucin protein, which is used for maintaining theintegrity and function of the intestines. Mucus, which is composed ofmucin and inorganic salts suspended in water, serve as a diffusionbarrier against contact with noxious substances such as gastric acid andsmoke. Mucus also acts as a lubricant to minimize shear stresses (G. K.Law, et al., Am J Physiol Gastrointest Liver Physiol 292:G1293-G1301,2007).

90% of dietary threonine is used in the gut for mucus synthesis. Mucinis continuously synthesized and is very resistant to intestinalproteolysis, and is therefore not very easily recycled. As such, asubstantial and consistent supply of threonine is used in order toeffectively maintain gut function and structure. As a result, it is veryimportant that the diet is rich with threonine in order to prevent mucusproduction from decreasing, which can lead to cancers in the gut,ulcers, etc. (G. K. Law, et al., Am J Physiol Gastrointest Liver Physiol292:G1293-G1301, 2007: A. Hamard, et al., Journal of NutritionalBiochemistry, October 2010, Volume 21, Issue 10, Pages 914-921). Due tothe importance of mucus to the integrity and structure of the gut,threonine supplementation can be useful in the prevention of gutdisorder including cancers, ulcers, infections, and erosions.

Threonine plays a key role in humoral immunity because threonine is amajor component of immunoglobulins, which are secreted by B lymphocytesin the blood. Once released, they reach the site of infection,recognize, bind, and inactivate their antigens. Because of the highthreonine content of immunoglobulins, a threonine deficiency may havenegatively affect immunoglobulin production, and thereby decrease immuneresponse. Threonine supplementation is essential for its role in theimmune response and can support leukemia patients, AIDS patients, andindividuals who have immunodeficiency. Additionally, it can supportthose susceptible to infection during the flu season, such as theelderly and small children, as well as throughout the year to strengthenimmune response.

Low Threonine

There exists a mechanistic understanding of how uncharged tRNAallosterically activates GCN2, leading to downstream phosphorylation oftranscription factors related to lipogenesis, protein synthesis, alongwith many biosynthetic pathways in eukaryotes (SREBP-1c, eIF2a, andGCN4p discussed below). Diets devoid of any EAAs remarkably trigger thissignaling within minutes after diet introduction (Hao et. Al., science2005). Signaling through SREBP-1c has been shown in vivo to havedramatic effects on mobilizing lipid stores by repressing genes relatedto lipogenesis. SREBP-1c has been shown to specifically act on hepaticlipid synthesis, and an ability to cause a hepatic steatosis phenotypeas well as increase in visceral fat mass (Knebel, B. et. Al.Liver-Specific Expression of Transcriptionally Active SREBP-1c IsAssociated with Fatty Liver and Increased Visceral Fat Mass. PLoS,2012). An unbalanced diet lacking Threonine has been shown to signalGCN2 for rats on a basal casein diet with 1-5.4% of an amino acidmixture supplemented lacking Threonine. Threonine deprivation, throughits action on GCN2, has an effect on SREBP-1c and decreased physiologicmeasures of liver weight (and fatty liver phenotype), adipose tissueweight, cholesterol/triglyceride content, and food intake. Drivingdecreased fat mass, while maintaining lean mass, provides a therapeuticopportunity in areas such as obesity, diabetes, and cardiovascularhealth.

Tryptophan:

Tryptophan is both an EAA that plays an important role in immunefunctions. For example, concentrations of tryptophan progressivelydecline due to chronic lung inflammation. This suggests that catabolismof tryptophan via the indoleamine 2,3-dioxygenase (IDO) appears to bevery important for function of macrophages and lymphocytes. Thus,antranilic acid (ANS) inhibits the production of proinflammatoryT-helper 1 cytokines and prevents autoimmune neuroinflammation.Tryptophan can be used to treat the inflammatory effects of certaindiseases include arthritis and asthma or other autoimmune diseases.

It is also a precursor for serotonin (5-HT) synthesis, aneurotransmitter that affects appetite, sleep and is widely implicatedin onset of depression. Abnormality in 5-HT activity in recovereddepression patients (on SSRIs or other neurotransmitter re-uptakeinhibitors) leads to an acute sensitivity to low levels of Tryptophan inthe bloodstream. 5-HT production can be increased 2-fold by oral intakeof free Tryptophan, indicating a role for Tryptophan administration indepression. Furthermore, Tryptophan can potentiate the effects of SSRIsdue to the apparent dependence on 5-HT availability for improvement inpatient outcome.

Tryptophan can furthermore be used to help in weight loss/maintenance,benefit those suffering from sleep disorders, recovery from travel andjet lag: in addition to those suffering from mood disorders likedepression or the effects of PMS.

Low Tryptophan

There exists a mechanistic understanding of how uncharged tRNAallosterically activates GCN2, leading to downstream phosphorylation oftranscription factors related to lipogenesis, protein synthesis, alongwith many biosynthetic pathways in eukaryotes (SREBP-1c, elF2a, andGCN4p discussed below). Diets devoid of any EAAs remarkably trigger thissignaling within minutes after diet introduction (Hao et. Al., science2005). Signaling through SREBP-1c has been shown in vivo to havedramatic effects on mobilizing lipid stores by repressing genes relatedto lipogenesis. SREBP-1c has been shown to specifically act on hepaticlipid synthesis, and an ability to cause a hepatic steatosis phenotypeas well as increase in visceral fat mass (Knebel. B. et. Al.Liver-Specific Expression of Transcriptionally Active SREBP-1c IsAssociated with Fatty Liver and Increased Visceral Fat Mass. PLoS,2012). Tryptophan deprivation, through its action on GCN2, has an effecton SREBP-1c and decreased physiologic measures of liver weight (andfatty liver phenotype), adipose tissue weight, cholesterol/triglyceridecontent, and food intake. Driving decreased fat mass, while maintaininglean mass, provides a therapeutic opportunity in areas such as obesity,diabetes, and cardiovascular health.

Tyrosine:

Tyrosine is a nonessential amino acid that is synthesized fromphenylalanine. It is used as a precursor for many importantneurotransmitters including, epinephrine, norepinephrine, and dopamine.Tyrosine helps produce melanin, and helps the organs that make andregulate hormones, like the adrenal gland, thyroid gland, and pituitarygland. Additionally, tyrosine is involved in the structure of almostevery protein in the body.

Tyrosine hydroxylase converts L-tyrosine into Levodopa usingtetrahydropteridine as a cofactor or by tyrosinase. The conversion thatis mediated by tyrosinase specifically oxidizes Levodopa to Dopaquinone,and levodopa is further decarboxylated to Dopamine by Dopadecarboxylase. Dopamine is a very important hormone andneurotransmitter, and plays a vital role in both mental and physicalhealth. Dopamine helps to control the brain's reward and pleasurecenters, helps to regulate movement and emotional responses, and enablesone to see rewards and take action to move towards those rewards. Theneurons that contain dopamine are clustered in the midbrain, in an areacalled the susbtantia nigra. In those afflicted with Parkinson'sdisease, the neurons that transmit dopamine in this area die resultingin an inability to control bodily movement. In order to relieve thesymptoms of Parkinson's disease, L-Dopa, which can be converted todopamine is given to the patients.

Tyrosine supplementation can help in the treatment of Parkinson'sdisease due to its role as a precursor to L-DOPA and dopamine.Additionally, it can be used in the treatment of those withemotional/psychiatric disorder like depression and in the treatment ofaddiction. Furthermore, it can promote learning by increasing thereward/pleasure response during learning difficult or complex conceptsor movements.

Dopamine, which is a monoamine catecholamine neurotransmitter, plays aregulatory role in the immune system. Neurotransmitters andneuropeptides that interact with specific receptors present inparticular immune effector cells are released by the immune system toinfluence the functions of these cells in the host against disease andother environmental stress. The immunoregulatory actions of dopaminehave been shown to be regulated via five different G protein-coupledreceptors that are present in target cells. There are two broad classesof these receptors: G1 and G2, which encompass the varying subtypes. TheDI class of receptors includes D2 and D5 subtypes, and increaseintracellular cAMP upon activation. The D2 class of receptors consistsof the D2, D3, and D4 subtypes, and has been reported to inhibitintracellular cAMP upon stimulation. Dopamine receptors have been foundon normal human leukocytes. Likewise, the lymphoid tissues havedopaminergic innervations through sympathetic nerves, which suggeststhat dopamine may be able to regulate the immune system effector cells(Basu, Sujit & Sarkar, Chandrani, Dopamine and immune system. SciTopics2010).

Dopamine affects T cells by activating the resting T cells andinhibiting the activation of stimulated T cells. In normal restingperipheral human T lymphocytes, dopamine activates the D2 and D3subclass of receptors, which in turn activates integrins (α4β1 andα5β1). These integrins are hetrodimeric transmembrane glycoproteins thatattach cells to the extracellular matrix component, fibronectin.Fibronectin is used for the trafficking and extravasation of T cellsacross the tissue barriers and blood vessels. Furthermore, dopamine actsthrough the D3 receptors to selectively induce the migration and homingof CD8+ T cells. Moreover, dopamine affects T cells by influencing thesecretions of cytokines by the T cells. When dopamine stimulates the D3and D1/D5 receptors, the secretion of TNF-α (a pleiotropic inflammatorycytokine) is increased. When the D2 receptors are stimulated, IL-10 (ananti-inflammatory cytokine) is induced to secrete. Dopamine, however,can inhibit the activated T cell receptor induced cell proliferation andsecretion of a number of cytokines like 11-2, IFN-γ and IL-4 through thedown-regulation of the expression of non-receptor tyrosine kinases Ickand fyn, which are important tyrosine kinases in the initiation of TCRactivation (Basu, Sujit & Sarkar, Chandrani Dopamine and immune system.SciTopics 2010).

The B cells have a very high expression of dopamine D2, D3, and D5receptors. Dopamine has the ability to inhibit the proliferation of theresting and the malignant B lymphocytes. Dopamine acts by promotingapoptosis in cycling B cells through oxidative stress. However, thisdopaminergic action has not been observed in resting lymphocytes,therefore suggesting a role in the prevention of cancer (Basu, Sujit &Sarkar, Chandrani, Dopamine and immune system. SciTopics 2010).

Tyrosine, as a precursor for Dopamine, can be used to improve immuneresponses and improve the overall immune system functionality. It canprovide a benefit to the elderly, women who are pregnant, children, andthose with compromised immune functions like AIDS patients and cancerpatients. It also can be given to teachers, those travelling, and anyonefrequently exposed to germs.

NE is synthesized in the adrenal medulla and postganglionic neurons inthe sympathetic nervous system by the β-oxidation of dopamine byβ-hydroxylase along with the cofactor ascorbate. It works by beingsecreted into the synaptic cleft where it stimulates adrenergicreceptors, and is then either degraded or up-taken by surrounding cells.As a cathecolamine, it does not cross the blood-brain barrier.

NE can be used to combat ADHD, depression, and hypotension. In terms ofattention disorders, like ADHD, medications prescribed tend to helpincrease levels of NE and dopamine. Furthermore, depression is typicallytreated with medications that inhibit the reuptake of serotonin and NEthereby increasing the amount of serotonin and NE that is available inthe postsynaptic cells in the brain. Recent evidence has suggested thatSNRIs may also increase dopamine transmission because if thenorepinephrine transporter ordinarily recycled dopamine as well, thenSNRIs will also enhance the dopaminergic transmission. As a result, theeffects antidepressants may also be associated with the increased NElevels may partly be due to the simultaneous increase in dopamine (inparticular in the prefrontal cortex of the brain).

NE is used to treat patients with critical hypotension. NE is avasopressor and acts on both α1 and α2 adrenergic receptors to causevasoconstriction, thereby increasing the blood pressure.

As a precursor for NE, Tyrosine can be used to treat attention disorderslike ADHD and ADD. Additionally, it can be used to treat those sufferingfrom depression, post-traumatic stress syndrome, and those with acutehypotension.

Epinephrine, which is popularly known as adrenaline, is a hormone thatis secreted by the medulla of the adrenal glands. Epinephrine isreleased in response to strong emotions such as fear or anger, whichcauses an increase in heart rate, muscle strength, blood pressure, andsugar metabolism. It is responsible for the flight or fight responsethat prepares the body for difficult or strenuous activity. Epinephrineis used as a stimulant during cardiac arrest, as a vasoconstrictorduring shock to increase blood pressure, and as a bronchodilator andantispasmodic in bronchial asthma. Epinephrine is not found in largequantities in the body, but is nevertheless very important in themaintenance of cardiovascular homeostasis because it has the ability todivert blood to tissues under stress. Epinephrine has this effect byinfluencing muscle contraction. Contraction of the muscles occursthrough the binding calmodulin to calcium ions when the concentration is10× larger than normal in the cell. The calcium-calmodulin complex thengoes on to activate the myosin light chain kinase, which thenphosphorylates the LC2 causing the contraction. Epinephrine binds to theepinephrine receptors, which activates adenylyl cyclase, and producescyclic AMP from ATP, cAMP activates a protein kinase which thusphosphorylates the myosin light chain kinase. This phosphorylated myosinlight chain kinase has a lower affinity for the calcium-calmodulincomplex, and is thus inactive. As such, the smooth muscle tissue isrelaxed. It is this action of epinephrine that makes it very useful intreating asthma, cardiac arrest, and anaphylactic shock. Tyrosine, as aprecursor for Epinephrine, can be used for patients who are at risk forcardiac arrest, those suffering from asthma, and those who are at riskfor anaphylactic shock.

Epinephrine is one of two main hormones that breakdown glycogen bybinding to a receptor on exterior of a liver cell. This binding causes aconformational change to take place thereby allowing G protein to bindand become active. The activation of the G-protein coupled receptorcauses a conformational change on the molecule to occur which causesadenylate cyclase to bind. Once adenylate cyclase binds the complex,adenylate cyclase breaks down ATP into cAMP, which then becomes thesecond messenger protein in this process and activates protein kinase.The activated protein kinase activates phosphorylase, which is an enzymethat catalyzes breaks down the glycogen to glucose. Tyrosine, as aprecursor for Epinephrine, can be used to improve athletic performanceby making glucose readily available to fuel exercise.

Melanin is a metabolite of Tyrosine, and is a powerful antioxidant.Additionally, it is influential in the inhibition of the production ofinflammatory cytokines and superoxide. When pro-inflammatory cytokinesare overproduced, it mediates the damaging effects of inflammation inpathologic conditions like rheumatoid arthritis, graft vs. hostreactions, cachexia, and sepsis syndrome. It has been found that melanininhibits ongoing cytokine synthesis, which strongly suggests thatmelanin may be useful as a superimposed therapy for conditions thatinvolve proinflammatory cytokines (Mohagheghpour N., et al., CellImmunol. 2000 Jan. 10; 199(1):25-36).

Tyrosine can be used in the treatment of rheumatoid arthritis, cachexia,sepsis syndrome, those with inflammation related to autoimmune disorder,and other inflammatory sequela of pathologic conditions.

Valine:

Valine is an EAA, and is also a BCAA. The BCAAs, including valine, serveas fuel sources for skeletal muscle during periods of metabolic stressby promoting protein synthesis, suppressing protein catabolism, andserving as substrates for gluconeogenesis. The BCAAs, including valine,are substrates for glutamine synthesis in animal tissues, and it hasbeen shown that glutamine may play a role in mediating the anaboliceffect of BCAAs in animals. Such an effect is likely to be important forthe lactating mammary gland because it produces more glutamine than ittakes up from arterial blood. Catabolism of BCAAs in the placentaresults in glutamine synthesis and its release into the fetalcirculation, which is a major source of the glutamine that circulates inthe fetus. This suggests that supplementing a diet with Valine as wellas the other BCAAs, or a combination thereof, may increase fetal growthin mammals. Additionally, Valine plays a direct role in the synthesis ofalanine, and therefore has a regulatory function with regards toalanine.

BCAAs have been shown to have anabolic effects on protein metabolism byincreasing the rate of protein synthesis and decreasing the rate ofprotein degradation in resting human muscle. Additionally, BCAAs areshown to have anabolic effects in human muscle during post enduranceexercise recovery. These effects are mediated through thephosphorylation of mTOR and sequential activation of 70-kD S6 proteinkinase (p70-kD S6), and eukaryotic initiation factor 4E-bindingprotein 1. P70-kD S6 is known for its role in modulating cell-cycleprogression, cell size, and cell survival. P70-kD S6 activation inresponse to mitogen stimulation up-regulates ribosomal biosynthesis andenhances the translational capacity of the cell (W-L An, et al., Am JPathol. 2003 August; 163(2): 591-607; E. Blomstrand, et al., J. Nutr.January 2006 136: 269S-273S). Eukaryotic initiation factor 4E-bindingprotein 1 is a limiting component of the multi-subunit complex thatrecruits 40S ribosomal subunits to the 5′ end of mRNAs. Activation ofp70 S6 kinase, and subsequent phosphorylation of the ribosomal proteinS6, is associated with enhanced translation of specific mRNAs.

BCAAs given to subjects during and after one session of quadricepsmuscle resistance exercise show an increase in mTOR, p70 S6 kinase, andS6 phosphorylation was found in the recovery period after the exercise.However, there was no such effect of BCAAs on Akt or glycogen synthasekinase 3 (GSK-3). Exercise without BCAA intake leads to a partialphosphorylation of p70 S6 kinase without activating the enzyme, adecrease in Akt phosphorylation, and no change in GSK-3. BCAA infusionalso increases p70 S6 kinase phosphorylation in an Akt-independentmanner in resting subjects. This mTOR activity regulates cellularprotein turnover (autophagy) and integrates insulin-like growth signalsto protein synthesis initiation across tissues. This biology has beendirectly linked to biogenesis of lean tissue mass in skeletal muscle,metabolic shifts in disease states of obesity and insulin resistance,and aging.

Valine plays a key role in muscle metabolism, tissue repair, and themaintenance of proper nitrogen balance in the body. As one of the threeBCAAs, it can be utilized as an energy source by muscle tissue. Valineis a glucogenic AA, and therefore provides glucose. Valine may be usefulin the treatment of liver and gallbladder disease. Additionally, valinemay be useful in correcting the type of severe AA deficiencies caused bydrug addiction. Furthermore, Valine has been found to promote mentalvigor, muscle coordination, and calm emotions. It may also be used toprevent muscle loss at high altitudes.

Valine supplementation can be used to improve athletic performance andmuscle formation, aid in drug addiction rehabilitation, to enhancemental vigor in elderly and growing children, prevent muscle loss thataccompanies aging, aid those suffering from hepatic disease, support thegrowing bodies of children, serve as a therapy for gallbladder and liverdisease, to increase lactation in mammals, to increase fetal growth inmammals, and improve the nutritive quality of foods given to thestarving populations.

Low Valine

In states of obesity and diabetes, animals have been shown to exhibitreduced hepatic autophagy, leading to increased insulin resistance.Autophagy is important for maintenance of the ER and cellularhomeostasis, which when stressed can lead to impaired insulinsensitivity. High fat diet feeding in animal models stresses the ER,while leading to depressed hepatic autophagy through over-stimulation ofmTORC1, which reinforces the progression towards insulin sensitivityimpaired beta cell function in diabetes. Reducing the level of systemicValine provides an opportunity to lower mTORC1 activity and restorehealthy levels of autophagy.

There exists a mechanistic understanding of how uncharged tRNAallosterically activates GCN2, leading to downstream phosphorylation oftranscription factors related to lipogenesis and protein synthesis,along with many biosynthetic pathways in eukaryotes (SREBP-1c, eIF2a,and GCN4p discussed below). Diets devoid of any EAAs remarkably triggerthis signaling within minutes after diet introduction (Hao et. Al.,science 2005). Signaling through SREBP-1c has been shown in vivo to havedramatic effects on mobilizing lipid stores by repressing genes relatedto lipogenesis. SREBP-le has been shown to specifically act on hepaticlipid synthesis, and an ability to cause a hepatic steatosis phenotypeas well as increase in visceral fat mass (Knebel, B. et. Al.Liver-Specific Expression of Transcriptionally Active SREBP-1c IsAssociated with Fatty Liver and Increased Visceral Fat Mass. PLoS,2012). Valine deprivation, through its action on GCN2, has an effect onSREBP-c and decreased physiologic measures of liver weight (and fattyliver phenotype), adipose tissue weight, cholesterol/triglyceridecontent and food intake. Driving decreased fat mass, while maintaininglean mass, provides a therapeutic opportunity in areas such as obesity,diabetes, and cardiovascular health.

In vitro analyses of amino acid pharmacology. As provided herein, aminoacids behave both as necessary substrates for the synthesis of newproteins and also serve as signaling molecules. Analysis of thepharmacological properties of a given amino acid is dependent on thecell line and model system utilized. For example, the amino acid leucinehas been shown to increase phosphorylation of the mammalian target ofrapamycin complex I and downstream targets involved in anabolism inskeletal muscle cells (Gran P & D Cameron-Smith. 2011. The actions ofexogenous leucine on mTOR signaling and amino acid transporters in humanmyotubes. BMC Physiol. 11:10). In vitro assays of amino acidpharmacology can also reveal auxotrophies in certain types of cancer.Auxotrophies to methionine have been reported in multiple immortalizedcancer cell lines (Cavuoto P & MF Fenech. 2012. A review of methioninedependency and the role of methionine restriction in cancer growthcontrol and life-span extension. Cancer Treat Rev. 38: 726-736).

An in vitro assay may be designed utilizing amino acids, proteindigests, or di- and tri-peptides as the independent or manipulatedvariable after identifying a relevant cell line. An appropriate cellline is selected based on its relevance as a model of cellularprocesses. For example, C2C12 (ATCC. CRL-1772) is a murine myoblast cellline that differentiates into myofibers and is used as a model ofskeletal muscle fiber differentiation and development. Cells aremaintained in a complete medium supplemented with fetal bovine serum upto 10% which supplies necessary growth factors, and penicillin andstreptomycin. Adherent cell lines are grown in T75 flasks with phenoliccaps for filtered gas exchange and incubated at 37° C. at 5% CO2 in ahumidified environment. Table AA lists cell lines that are used to assayamino acid pharmacology. For an in vitro assay, cells are seeded in T75flasks, 6-, 12-, 24-, 48- or 96-well plates at an appropriate celldensity, determined empirically. Following an incubation period thecomplete growth medium is replaced with medium deficient in the testarticle. Following a period of medium depletion the test article isadded in the appropriate medium. Following the treatment period, therelevant dependent variable is measured.

TABLE AA List of exemplary cell lines utilized in vitro assays of aminoacid pharmacology. Tissue Cell Line Species or Cell Type Systems ModeledC2C12 Mus Skeletal muscle Skeletal muscle growth musculus anddifferentiation RSkMC Rattus Skeletal muscle Skeletal muscle growthnorvegicus and differentiation 3T3-L1 Mus Embryo White adipose tissuemusculus development CHO-K1 Cricetulus Ovary Heterologous proteingriseus expression FHs 74 Int Homo Small intestine Gastrointestinal andsapiens enteroendocrine systems 293T Homo Embryonic Heterologous proteinsapiens kidney expression IEC-6 Rattus Small intestine/ Gastrointestinaland norvegicus epithelium enteroendocrine systems NCI-H716 Homo CecumGastrointestinal and sapiens enteroendocrine systems STC-1 Mus IntestineGastrointestinal and musculus enteroendocrine systems MCF-7 Homo LungBreast cancer sapiens adenocarcinoma LNCaP Homo Prostate Prostate cancerclone FGC sapiens carcinoma Homo Prostate Prostate cancer PC-3 sapiensadenocarcinoma

See, e.g., Wu, G. Amino acids: Metabolism, functions, and nutrition.Amino Acids 37(1):1-17 (2009); Wu, G. Functional amino acids innutrition and health. Amino Acids 45(3):407-11 (2013); Schworer, C.Glucagon-induced autophagy and proteolysis in rat liver: Mediation byselective deprivation of intracellular amino acids. PNAS 76(7):3169-73(1979); Codongo, P. Autophagy: A Potential Link between Obesity andInsulin Resistance. Cell Metabolism 11(6):449-51 (2010); Leong, H et.al. Short-term arginine deprivation results in large-scale modulation ofhepatic gene expression in both normal and tumor cells: microarraybioinformatic analysis. Nutrition and metabolism 3:37 (2006); Harbrecht,B. G. Glutathione regulates nitric oxide synthase in culturedhepatocytes. Annals of Surgery 225(1): 76-87 (1997); Watermelon juice: apotential functional drunk for sore muscle relief in athletes. J. Agric.Food Chem. 61(31):7522-8 (2013).

Secreted Nutritive Polypeptides.

In another aspect, provided are nutritive polypeptides that contain theamino acid sequences of edible species polypeptides, which areengineered to be secreted from unicellular organisms and purifiedtherefrom. Such nutritive polypeptides can be endogenous to the hostcell or exogenous, and can be naturally secreted in either thepolypeptide or the host cell, or both, and are engineered for secretionof the nutritive polypeptide.

Advantageous properties of a nutritive polypeptide include the abilityto be expressed and secreted in a host cell, solubility in a widevariety of solvents, and when consumed by an intended subject,nutritional benefit, reduced allergenicity or non-allergenicity, lack oftoxicity, and digestibility. Such properties can be weighted based, atleast in part, on the intended consumer and the reason(s) forconsumption of the nutritive polypeptide (e.g., for general health,muscle anabolism, immune health, or treatment or prevention of adisease, disorder or condition). One or multiple nutritional criteriaare satisfied for example, by computing the mass fractions of allrelevant amino acid(s) based on primary sequence.

By way of non-limiting examples, polypeptides of the present inventionare provided in Table 1. The Predicted leader column shows the sequenceindices of predicted leaders (if a leader exists). The Fragment Indicescolumn shows the sequence indices of fragment sequences. The DBID columnlists either the UniProt or GenBank Accession numbers for each sequenceas available as of Sep. 24, 2014, each of which is herein incorporatedby reference. DBIDs with only numerical characters are from a GenBankdatabase, and those with mixed alphabetical/numerical characters arefrom a UniProt database.

Nucleic Acids

Also provided herein are nucleic acids encoding polypeptides orproteins. In some embodiments the nucleic acid is isolated. In someembodiments the nucleic acid is purified.

In some embodiments of the nucleic acid, the nucleic acid comprises anucleic acid sequence that encodes a first polypeptide sequencedisclosed herein. In some embodiments of the nucleic acid, the nucleicacid consists of a nucleic acid sequence that encodes a firstpolypeptide sequence disclosed herein. In some embodiments of thenucleic acid, the nucleic acid comprises a nucleic acid sequence thatencodes a protein disclosed herein. In some embodiments of the nucleicacid, the nucleic acid consists of a nucleic acid sequence that encodesa protein disclosed herein. In some embodiments of the nucleic acid thenucleic acid sequence that encodes the first polypeptide sequence isoperatively linked to at least one expression control sequence. Forexample, in some embodiments of the nucleic acid the nucleic acidsequence that encodes the first polypeptide sequence is operativelylinked to a promoter such as a promoter described herein.

Accordingly, in some embodiments the nucleic acid molecule of thisdisclosure encodes a polypeptide or protein that itself is a polypeptideor protein. Such a nucleic acid molecule can be referred to as a“nucleic acid.” In some embodiments the nucleic acid encodes apolypeptide or protein that itself comprises at least one of: a) a ratioof branched chain amino acid residues to total amino acid residues of atleast 24%; b) a ratio of Leu residues to total amino acid residues of atleast 11%; and c) a ratio of essential amino acid residues to totalamino acid residues of at least 49%. In some embodiments the nucleicacid comprises at least 10 nucleotides, at least 20 nucleotides, atleast 30 nucleotides, at least 40 nucleotides, at least 50 nucleotides,at least 60 nucleotides, at least 70 nucleotides, at least 80nucleotides, at least 90 nucleotides, at least 100 nucleotides, at least200 nucleotides, at least 300 nucleotides, at least 400 nucleotides, atleast 500 nucleotides, at least 600 nucleotides, at least 700nucleotides, at least 800 nucleotides, at least 900 nucleotides, atleast 1,000 nucleotides. In some embodiments the nutritive nucleic acidcomprises from 10 to 100 nucleotides, from 20 to 100 nucleotides, from10 to 50 nucleotides, or from 20 to 40 nucleotides. In some embodimentsthe nucleic acid comprises all or part of an open reading frame thatencodes an edible species polypeptide or protein. In some embodimentsthe nucleic acid consists of an open reading frame that encodes afragment of an edible species protein, wherein the open reading framedoes not encode the complete edible species protein.

In some embodiments the nucleic acid is a cDNA.

In some embodiments nucleic acid molecules are provided that comprise asequence that is at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%,98%, 99%, or 99.9% identical to an edible species nucleic acid. In someembodiments nucleic acids are provided that hybridize under stringenthybridization conditions with at least one reference nucleic acid.

The nucleic acids and fragments thereof provided in this disclosuredisplay utility in a variety of systems and methods. For example, thefragments can be used as probes in various hybridization techniques.Depending on the method, the target nucleic acid sequences can be eitherDNA or RNA. The target nucleic acid sequences can be fractionated (e.g.,by gel electrophoresis) prior to the hybridization, or the hybridizationcan be performed on samples in situ. One of skill in the art willappreciate that nucleic acid probes of known sequence find utility indetermining chromosomal structure (e.g., by Southern blotting) and inmeasuring gene expression (e.g., by Northern blotting). In suchexperiments, the sequence fragments are preferably detectably labeled,so that their specific hydridization to target sequences can be detectedand optionally quantified. One of skill in the art will appreciate thatthe nucleic acid fragments of this disclosure can be used in a widevariety of blotting techniques not specifically described herein.

It should also be appreciated that the nucleic acid sequence fragmentsdisclosed herein also find utility as probes when immobilized onmicroarrays. Methods for creating microarrays by deposition and fixationof nucleic acids onto support substrates are well known in the art.Reviewed in DNA Microarrays: A Practical Approach (Practical ApproachSeries), Schena (ed.), Oxford University Press (1999) (ISBN:0199637768); Nature Genet. 21(1)(suppl): 1-60 (1999); MicroarrayBiochip: Tools and Technology, Schena (ed.), Eaton PublishingCompany/BioTechniques Books Division (2000) (ISBN: 1881299376), thedisclosures of which are incorporated herein by reference in theirentireties. Analysis of, for example, gene expression using microarrayscomprising nucleic acid sequence fragments, such as the nucleic acidsequence fragments disclosed herein, is a well-established utility forsequence fragments in the field of cell and molecular biology. Otheruses for sequence fragments immobilized on microarrays are described inGerhold et al., Trends Biochem. Sci. 24:168-173 (1999) and Zweiger.Trends Biotechnol. 17:429-436 (1999); DNA Microarrays: A PracticalApproach (Practical Approach Series), Schena (ed.), Oxford UniversityPress (1999) (ISBN: 0199637768); Nature Genet. 21(1)(suppl):1-60 (1999);Microarray Biochip: Tools and Technology, Schena (ed.), Eaton PublishingCompany/BioTechniques Books Division (2000) (ISBN: 1881299376).

Expression

Vectors

Also provided are one or more vectors, including expression vectors,which comprise at least one of the nucleic acid molecules disclosedherein, as described further herein. In some embodiments, the vectorscomprise at least one isolated nucleic acid molecule encoding a proteinas disclosed herein. In alternative embodiments, the vectors comprisesuch a nucleic acid molecule operably linked to one or more expressioncontrol sequence. The vectors can thus be used to express at least onerecombinant protein in a recombinant microbial host cell. In someaspects, a vector or set of vectors can include a nucleic acid sequencecoding for a signal peptide, e.g., to cause secretion of a proteindisclosed herein. See below for further discussion of signal peptidesand secretion.

Suitable vectors for expression of nucleic acids in microorganisms arewell known to those of skill in the art. Suitable vectors for use incyanobacteria are described, for example, in Heidorn et al., “SyntheticBiology in Cyanobacteria: Engineering and Analyzing Novel Functions,”Methods in Enzymology, Vol. 497, Ch. 24 (2011). Exemplary replicativevectors that can be used for engineering cyanobacteria as disclosedherein include pPMQAK1, pSL1211, pFC1, pSB2A, pSCR119/202, pSUN119/202,pRL2697, pRL25C, pRL1050, pSG111M, and pPBH201.

Other vectors such as pJB161 which are capable of receiving nucleic acidsequences disclosed herein may also be used. Vectors such as pJB161comprise sequences which are homologous with sequences present inplasmids endogenous to certain photosynthetic microorganisms (e.g.,plasmids pAQ1, pAQ3, and pAQ4 of certain Synechococcus species).Examples of such vectors and how to use them is known in the art andprovided, for example, in Xu et al., “Expression of Genes inCyanobacteria: Adaptation of Endogenous Plasmids as Platforms forHigh-Level Gene Expression in Synechococcus sp. PCC 7002,” Chapter 21 inRobert Carpentier (ed.), “Photosynthesis Research Protocols,” Methods inMolecular Biology, Vol. 684, 2011, which is hereby incorporated hereinby reference. Recombination between pJB161 and the endogenous plasmidsin vivo yield engineered microbes expressing the genes of interest fromtheir endogenous plasmids. Alternatively, vectors can be engineered torecombine with the host cell chromosome, or the vector can be engineeredto replicate and express genes of interest independent of the host cellchromosome or any of the host cell's endogenous plasmids.

A further example of a vector suitable for recombinant proteinproduction is the pET system (Novagen®). This system has beenextensively characterized for use in E. coli and other microorganisms.In this system, target genes are cloned in pET plasmids under control ofstrong bacteriophage T7 transcription and (optionally) translationsignals; expression is induced by providing a source of T7 RNApolymerase in the host cell. T7 RNA polymerase is so selective andactive that, when fully induced, almost all of the microorganism'sresources are converted to target gene expression: the desired productcan comprise more than 50% of the total cell protein a few hours afterinduction. It is also possible to attenuate the expression level simplyby lowering the concentration of inducer. Decreasing the expressionlevel may enhance the soluble yield of some target proteins. In someembodiments this system also allows for maintenance of target genes in atranscriptionally silent un-induced state.

In some embodiments of using this system, target genes are cloned usinghosts that do not contain the T7 RNA polymerase gene, thus alleviatingpotential problems related to plasmid instability due to the productionof proteins potentially toxic to the host cell. Once established in anon-expression host, target protein expression can be initiated eitherby infecting the host with λCE6, a phage that carries the T7 RNApolymerase gene under the control of the λμL and pI promoters, or bytransferring the plasmid into an expression host containing achromosomal copy of the T7 RNA polymerase gene under lacUV5 control. Inthe second case, expression is induced by the addition of IPTG orlactose to the bacterial culture or using an autoinduction medium. Otherplasmids systems that are controlled by the lac operator, but do notrequire the T7 RNA polymerase gene and rely upon E. coli's native RNApolymerase include the pTrc plasmid suite (Invitrogen) or pQE plamidsuite (QIAGEN).

In other embodiments it is possible to clone directly into expressionhosts. Two types of T7 promoters and several hosts that differ in theirstringency of suppressing basal expression levels are available,providing great flexibility and the ability to optimize the expressionof a wide variety of target genes.

Suitable vectors for expression of nucleic acids in mammalian cellstypically comprise control functions provided by viral regulatoryelements. For example, commonly used promoters are derived from polyomavirus, Adenovirus 2, cytomegalovirus, or Simian Virus 40.

Promoters

Promoters useful for expressing the recombinant genes described hereininclude both constitutive and inducible/repressible promoters. Examplesof inducible/repressible promoters include nickel-inducible promoters(e.g., PnrsA, PnrsB; see, e.g., Lopez-Mauy et al., Cell (2002) v. 43:247-256) and urea repressible promoters such as PnirA (described in,e.g., Qi et al., Applied and Environmental Microbiology (2005) v. 71:5678-5684). Additional examples of inducible/repressible promotersinclude PnirA (promoter that drives expression of the nirA gene, inducedby nitrate and repressed by urea) and Psuf (promoter that drivesexpression of the suiB gene, induced by iron stress). Examples ofconstitutive promoters include Pcpc (promoter that drives expression ofthe cpc operon), Prbc (promoter that drives expression of rubisco),PpsbAII (promoter that drives expression of PpsbAII), Pcro (lambda phagepromoter that drives expression of cro). In other embodiments, a PaphIIand/or a laclq-Ptrc promoter can used to control expression. Wheremultiple recombinant genes are expressed in an engineered microorganism,the different genes can be controlled by different promoters or byidentical promoters in separate operons, or the expression of two ormore genes can be controlled by a single promoter as part of an operon.

Further non-limiting examples of inducible promoters may include, butare not limited to, those induced by expression of an exogenous protein(e.g., T7 RNA polymerase, SP6 RNA polymerase), by the presence of asmall molecule (e.g., IPTG, galactose, tetracycline, steroid hormone,abscisic acid), by absence of small molecules (e.g., CO2, iron,nitrogen), by metals or metal ions (e.g., copper, zinc, cadmium,nickel), and by environmental factors (e.g., heat, cold, stress, lightdarkness), and by growth phase. In some embodiments, the induciblepromoter is tightly regulated such that in the absence of induction,substantially no transcription is initiated through the promoter. Insome embodiments, induction of the promoter does not substantially altertranscription through other promoters. Also, generally speaking, thecompound or condition that induces an inducible promoter is notnaturally present in the organism or environment where expression issought.

In some embodiments, the inducible promoter is induced by limitation ofCO₂ supply to a cyanobacteria culture. By way of non-limiting example,the inducible promoter can be the promoter sequence of Synechocystis PCC6803 that are up-regulated under the CO₂-limitation conditions, such asthe cmp genes, ntp genes, ndh genes, sbt genes, chp genes, and rbcgenes, or a variant or fragment thereof.

In some embodiments, the inducible promoter is induced by ironstarvation or by entering the stationary growth phase. In someembodiments, the inducible promoter can be variant sequences of thepromoter sequence of cyanobacterial genes that are up-regulated underFe-starvation conditions such as isiA, or when the culture enters thestationary growth phase, such as isiA, phrA, sigC, sigB, and sigHgenes,or a variant or fragment thereof.

In some embodiments, the inducible promoter is induced by a metal ormetal ion. By way of non-limiting example, the inducible promoter can beinduced by copper, zinc, cadmium, mercury, nickel, gold, silver, cobalt,and bismuth or ions thereof. In some embodiments, the inducible promoteris induced by nickel or a nickel ion. In some embodiments, the induciblepromoter is induced by a nickel ion, such as Ni²⁺. In another exemplaryembodiment, the inducible promoter is the nickel inducible promoter fromSynechocystis PCC 6803. In another embodiment, the inducible promotercan be induced by copper or a copper ion. In yet another embodiment, theinducible promoter can be induced by zinc or a zinc ion. In stillanother embodiment the inducible promoter can be induced by cadmium or acadmium ion. In yet still another embodiment, the inducible promoter canbe induced by mercury or a mercury ion. In an alternative embodiment,the inducible promoter can be induced by gold or a gold ion. In anotheralternative embodiment, the inducible promoter can be induced by silveror a silver ion. In yet another alternative embodiment, the induciblepromoter can be induced by cobalt or a cobalt ion. In still anotheralternative embodiment, the inducible promoter can be induced by bismuthor a bismuth ion.

In some embodiments, the promoter is induced by exposing a cellcomprising the inducible promoter to a metal or metal ion. The cell canbe exposed to the metal or metal ion by adding the metal to themicrobial growth media. In certain embodiments, the metal or metal ionadded to the microbial growth media can be efficiently recovered fromthe media. In other embodiments, the metal or metal ion remaining in themedia after recovery does not substantially impede downstream processingof the media or of the bacterial gene products.

Further non-limiting examples of constitutive promoters includeconstitutive promoters from Gram-negative bacteria or a bacteriophagepropagating in a Gram-negative bacterium. For instance, promoters forgenes encoding highly expressed Gram-negative gene products can be used,such as the promoter for Lpp. OmpA, rRNA, and ribosomal proteins.Alternatively, regulatable promoters can be used in a strain that lacksthe regulatory protein for that promoter. For instance P_(lac), P_(tac),and P_(trc), can be used as constitutive promoters in strains that lackLac1. Similarly, P22 P_(R) and P_(L) can be used in strains that lackthe lambda C2 repressor protein, and lambda P_(R) and P_(L) can be usedin strains that lack the lambda C1 repressor protein. In one embodiment,the constitutive promoter is from a bacteriophage. In another embodimentthe constitutive promoter is from a Salmonella bacteriophage. In yetanother embodiment, the constitutive promoter is from a cyanophage. Insome embodiments, the constitutive promoter is a Synechocystis promoter.For instance, the constitutive promoter can be the PpsbAll promoter orits variant sequences, the Prbc promoter or its variant sequences, theP_(cpc) promoter or its variant sequences, and the PrnpB promoter or itsvariant sequences.

Hosts

Also provided are host cells transformed with the nucleic acid moleculesor vectors disclosed herein, and descendants thereof. In someembodiments the host cells are microbial cells. In some embodiments, thehost cells carry the nucleic acid sequences on vectors, which may butneed not be freely replicating vectors. In other embodiments, thenucleic acids have been integrated into the genome of the host cellsand/or into an endogenous plasmid of the host cells. The transformedhost cells find use, e.g., in the production of recombinant proteinsdisclosed herein.

A variety of host microorganisms can be transformed with a nucleic acidsequence disclosed herein and can in some embodiments be used to producea recombinant protein disclosed herein. Suitable host microorganismsinclude both autotrophic and heterotrophic microbes. In someapplications the autotrophic microorganisms allows for a reduction inthe fossil fuel and/or electricity inputs required to make a proteinencoded by a recombinant nucleic acid sequence introduced into the hostmicroorganism. This, in turn, in some applications reduces the costand/or the environmental impact of producing the protein and/or reducesthe cost and/or the environmental impact in comparison to the costand/or environmental impact of manufacturing alternative proteins, suchas whey, egg, and soy. For example, the cost and/or environmental impactof making a protein disclosed herein using a host microorganism asdisclosed herein is in some embodiments lower that the cost and/orenvironmental impact of making whey protein in a form suitable for humanconsumption by processing of cow's milk.

Non-limiting examples of heterotrophs include Escherichia coli,Salmonella typhimurium, Bacillus subtilis, Bacillus megaterium,Corynebacterium glutamicum, Streptomyces coelicolor, Streptomyceslividans, Streptomyces vanezuelae, Streptomyces roseosporus,Streptomyces fradiae, Streptomyces griseus, Streptomyces calvuligerus,Streptomyces hygroscopicus, Streptomyces platensis, Saccharopolysporaerythraea, Corynebacterium glutamicum, Aspergillus niger, Aspergillusnidulans, Aspergillus oryzae, Aspergillus terreus, Aspergillus sojae,Penicillium chrysogenum, Trichoderma reesei, Clostridium acetobutylicum,Clostridium beijerinckii, Clostridium thermocellum, Fusibacterpaucivorans, Saccharomyces cerevisiae. Saccharomyces boulardii. Pichiapastoris, and Pichia stipitis.

Photoautotrophic microrganisms include eukaryotic algae, as well asprokaryotic cyanobacteria, green-sulfur bacteria, green non-sulfurbacteria, purple sulfur bacteria, and purple non-sulfur bacteria.Extremophiles are also contemplated as suitable organisms. Suchorganisms are provided, e.g., in Mixotrophic organisms are also suitableorganisms. Algae and cyanobacteria are contemplated as suitableorganisms. See the organisms disclosed in, e.g., PCT/US2013/032232,filed Mar. 15, 2013, PCT:/US2013/032180, filed Mar. 15, 2013.PCT/US2013/032225, filed Mar. 15, 2013, PCT/US2013/032218, filed Mar.15, 2013. PCT/US2013/032212, filed Mar. 15, 2013, PCT/US2013/032206,filed Mar. 15, 2013, and PCT/US2013/038682, filed Apr. 29, 2013

Yet other suitable organisms include synthetic cells or cells producedby synthetic genomes as described in Venter et al. US Pat. Pub. No.2007/0264688, and cell-like systems or synthetic cells as described inGlass et al. US Pat. Pub. No. 2007/0269862.

Still other suitable organisms include Escherichia coli, Acetobacteraceti, Bacillus subtilis, yeast and fungi such as Clostridiumljungdahlii, Clostridium thermocellum, Penicillium chrysogenum, Pichiapastoris, Saccharomyces cerevisiae, Schizosaccharomyces pombe,Pseudomonas fluorescens, or Zymomonas mobilis. In some embodiments thoseorganisms are engineered to fix carbon dioxide while in otherembodiments they are not.

In some embodiments eukaryotic cells, such as insect cells or mammaliancells, such as human cells are used as host cells. Vectors andexpression control sequences including promoters and enhancers are wellknown for such cells. Examples of useful mammalian host cell lines forthis purpose are monkey kidney CV1 line transformed by SV40 (COS-7, ATCCCRL 1651): human embryonic kidney line (293 or 293 cells subcloned forgrowth in suspension culture, Graham et al., J. Gen Virol. 36:59(1977)); baby hamster kidney cells (BHK, ATCC CCL 10); Chinese hamsterovary cells/-DHFR (CHO, Urlaub et al., Proc. Natl. Acad. Sci. USA77:4216 (1980)); mouse sertoli cells (TM4, Mather, Biol. Reprod.23:243-251 (1980)); monkey kidney cells (CV1 ATCC CCL 70); African greenmonkey kidney cells (VERO-76, ATCC CRL-1587); human cervical carcinomacells (HELA, ATCC CCL 2); canine kidney cells (MDCK, ATCC CCL 34);buffalo rat liver cells (BRL 3A, ATCC CRL 1442): human lung cells (W138.ATCC CCL 75); human liver cells (Hep G2, HB 8065); mouse mammary tumor(MMT 060562, ATCC CCL51); TRI cells (Mather et al., Annals N.Y. Acad.Sci. 383:44-68 (1982)); MRC 5 cells; FS4 cells; and a human hepatomaline (Hep G2).

Transfection

Proteins can be produced in a host cell using, for example, acombination of recombinant DNA techniques and gene transfection methodsas is well known in the art (e.g., Morrison, S. (1985) Science229:1202). For expression of the protein, the expression vector(s)encoding the protein is transfected into a host cell by standardtechniques. The various forms of the term transfection are intended toencompass a wide variety of techniques commonly used for theintroduction of exogenous DNA into a prokaryotic or eukaryotic hostcell, e.g., electroporation, calcium-phosphate precipitation,DEAE-dextran transfection and the like.

Production

Skilled artisans are aware of many suitable methods available forculturing recombinant cells to produce (and optionally secrete) aprotein as disclosed herein, as well as for purification and/orisolation of expressed proteins. The methods chosen for proteinpurification depend on many variables, including the properties of theprotein of interest, its location and form within the cell, the vector,host strain background, and the intended application for the expressedprotein. Culture conditions can also have an effect on solubility andlocalization of a given target protein. Many approaches can be used topurify target proteins expressed in recombinant microbial cells asdisclosed herein, including without limitation ion exchange and gelfiltration.

In some embodiments a peptide fusion tag is added to the recombinantprotein making possible a variety of affinity purification methods thattake advantage of the peptide fusion tag. In some embodiments, the useof an affinity method enables the purification of the target protein tonear homogeneity in one step. Purification may include cleavage of partor all of the fusion tag with enterokinase, factor Xa, thrombin, or HRV3 C proteases, for example. In some embodiments, before purification oractivity measurements of an expressed target protein, preliminaryanalysis of expression levels, cellular localization, and solubility ofthe target protein is performed. The target protein can be found in anyor all of the following fractions: soluble or insoluble cytoplasmicfractions, periplasm, or medium. Depending on the intended application,preferential localization to inclusion bodies, medium, or theperiplasmic space can be advantageous, in some embodiments, for rapidpurification by relatively simple procedures.

While Escherichia coli is widely regarded as a robust host forheterologous protein expression, it is also widely known thatover-expression of many proteins in this host is prone to aggregation inthe form of insoluble inclusion bodies. One of the most commonly usedmethods for either rescuing inclusion body formation, or to improve thetiter of the protein itself, is to include an amino-terminalmaltose-binding protein (MBP) (Austin B P, Nallamsetty S, Waugh D S.Hexahistidine-tagged maltose-binding protein as a fusion partner for theproduction of soluble recombinant proteins in Escherichia coli. MethodsMol Biol. 2009:498:157-72), or small ubiquitin-related modifier (SUMO)(Saitoh H, Uwada J, Azusa K. Strategies for the expression ofSUMO-modified target proteins in Escherichia coli. Methods Mol Biol.2009; 497:211-21; Malakhov M P, Mattern M R, Malakhova O A, Drinker M,Weeks S D, Butt T R. SUMO fusions and SUMO-specific protease forefficient expression and purification of proteins. J Struct FunctGenomics. 2004:5(1-2):75-86; Panavas T, Sanders C, Butt T R. SUMO fusiontechnology for enhanced protein production in prokaryotic and eukaryoticexpression systems. Methods Mol Biol. 2009; 497:303-17) fusion to theprotein of interest. These two proteins are expressed extremely well,and in the soluble form, in Escherichia coli such that the protein ofinterest is also effectively produced in the soluble form. The proteinof interest can be cleaved by designing a site specific proteaserecognition sequence (such as the tobacco etch virus (TEV) protease)in-between the protein of interest and the fusion protein. In someembodiments, a protein of interest can be present in an inclusion body;in some aspects the inclusion body can be formulated for delivery to asubject. Formulation is discussed in further detail below.

In some embodiments the protein is initially not folded correctly or isinsoluble. A variety of methods are well known for refolding ofinsoluble proteins. Most protocols comprise the isolation of insolubleinclusion bodies by centrifugation followed by solubilization underdenaturing conditions. The protein is then dialyzed or diluted into anon-denaturing buffer where refolding occurs. Because every proteinpossesses unique folding properties, the optimal refolding protocol forany given protein can be empirically determined by a skilled artisan.Optimal refolding conditions can, for example, be rapidly determined ona small scale by a matrix approach, in which variables such as proteinconcentration, reducing agent, redox treatment, divalent cations, etc.,are tested. Once the optimal concentrations are found, they can beapplied to a larger scale solubilization and refolding of the targetprotein.

In some embodiments the protein does not comprise a tertiary structure.In some embodiments less than half of the amino acids in the proteinparticipate in a tertiary structure. In some embodiments the proteindoes not comprise a secondary structure. In some embodiments less thanhalf of the amino acids in the protein participate in a secondarystructure. Recombinant proteins can be isolated from a culture of cellsexpressing them in a state that comprises one or more of thesestructural features. In some embodiments the tertiary structure of arecombinant protein is reduced or eliminated after the protein isisolated from a culture producing it. In some embodiments the secondarystructure of a recombinant protein is reduced or eliminated after theprotein is isolated from a culture producing it.

In some embodiments a CAPS buffer at alkaline pH in combination withN-lauroylsarcosine is used to achieve solubility of the inclusionbodies, followed by dialysis in the presence of DTT to promoterefolding. Depending on the target protein, expression conditions, andintended application, proteins solubilized from washed inclusion bodiescan be >90% homogeneous and may not require further purification.Purification under fully denaturing conditions (before refolding) ispossible using His.Tag® fusion proteins and His.Bind® immobilized metalaffinity chromatography (Novogen®). In addition, S.Tag™, T7.Tag®, andStrep.Tag® II fusion proteins solubilized from inclusion bodies using 6M urea can be purified under partially denaturing conditions by dilutionto 2 M urea (S*Tag and T7.Tag) or 1 M urea (Strep.Tag II) prior tochromatography on the appropriate resin. Refolded fusion proteins can beaffinity purified under native conditions using His.Tag, S.Tag,Strep.Tag II, and other appropriate affinity tags (e.g., GST.Tag™, andT7-Tag) (Novogent).

In some embodiments the protein is an endogenous protein of the hostcell used to express it. That is, the cellular genome of the host cellcomprises an open reading frame that encodes the recombinant protein. Insome embodiments regulatory sequences sufficient to increase expressionof the protein are inserted into the host cell genome and operativelylinked to the endogenous open reading frame such that the regulatorysequences drive overexpression of the recombinant protein from arecombinant nucleic acid. In some embodiments heterologous nucleic acidsequences are fused to the endogenous open reading frame of the proteinand cause the protein to be synthesized comprising a hetgerologous aminoacid sequence that changes the cellular trafficking of the recombinantprotein, such as directing it to an organelle or to a secretion pathway.In some embodiments an open reading frame that encodes the endogeneoushost cell protein is introduced into the host cell on a plasmid thatfurther comprises regulatory sequences operatively linked to the openreading frame. In some embodiments the recombinant host cell expressesat least 2 times, at least 3 times, at least 4 times, at least 5 times,at least 10 times, or at least 20 times, at least 30 times, at least 40times, at least 50 times, or at least 100 times more of the recombinantprotein than the amount of the protein produced by a similar host cellgrown under similar conditions.

Production of Recombinant Proteins in Plants

Nutritive polypeptides can be produced recombinantly from plants,including but not limited to those organisms and methods of productiondisclosed in PCT/US2013/032232, filed Mar. 15, 2013, PCT/US2013/032180,filed Mar. 15, 2013, PCT/US2013/032225, filed Mar. 15, 2013,PCT/US2013/032218, filed Mar. 15, 2013, PCT/US2013/032212, filed Mar.15, 2013, PCT/US2013/032206, filed Mar. 15, 2013, and PCT/US2013/038682,filed Apr. 29, 2013 and any phylogenetically related organisms, andother methods of production known in the art.

Purification

Secreted

It is generally recognized that nearly all secreted bacterial proteins,and those proteins from other unicellular hosts, are synthesized aspre-proteins that contain N-terminal sequences known as signal peptides.These signal peptides influence the final destination of the protein andthe mechanisms by which they are transported. Most signal peptides canbe placed into one of four groups based on their translocation mechanism(e.g., Sec- or Tat-mediated) and the type of signal peptidase used tocleave the signal peptide from the preprotein. Also provided areN-terminal signal peptides containing a lipoprotein signal peptide.Although proteins carrying this type of signal are transported via theSec translocase, their peptide signals tend to be shorter than normalSec-signals and they contain a distinct sequence motif in the C-domainknown as the lipo box (L(AS)(GA)C) at the −3 to +1 position. Thecysteine at the +1 position is lipid modified following translocationwhereupon the signal sequence is cleaved by a type 11 signal peptidase.Also provided are type IV or prepilin signal peptides, wherein type IVpeptidase cleavage domains are localized between the N- and H-domainrather than in the C-domain common in other signal peptides.

As provided herein, the signal peptides can be attached to aheterologous polypeptide sequence (i.e., different than the protein thesignal peptide is derived or obtained from) containing a nutritivepolypeptide, in order to generate a recombinant nutritive polypeptidesequence. Alternatively, if a nutritive polypeptide is naturallysecreted in the host organism, it can be sufficient to use the nativesignal sequence or a variety of signal sequences that directs secretion.In some embodiments of the nutritive polypeptides, the heterologousnutritive polypeptide sequence attached to the carboxyl terminus of thesignal peptide is an edible species eukaryotic protein, a mutein orderivative thereof, or a polypeptide nutritional domain. In otherembodiments of the polypeptide, the heterologous nutritive polypeptidesequence attached to the carboxyl terminus of the signal peptide is anedible species intracellular protein, a mutein or derivative thereof, ora polypeptide nutritional domain.

Purification of Nutritive Polypeptides.

Also provided are methods for recovering the secreted nutritivepolypeptide from the culture medium. In some embodiments the secretednutritive polypeptide is recovered from the culture medium during theexponential growth phase or after the exponential growth phase (e.g., inpre-stationary phase or stationary phase). In some embodiments thesecreted nutritive polypeptide is recovered from the culture mediumduring the stationary phase. In some embodiments the secreted nutritivepolypeptide is recovered from the culture medium at a first time point,the culture is continued under conditions sufficient for production andsecretion of the recombinant nutritive polypeptide by the microorganism,and the recombinant nutritive polypeptide is recovered from the culturemedium at a second time point. In some embodiments the secretednutritive polypeptide is recovered from the culture medium by acontinuous process. In some embodiments the secreted nutritivepolypeptide is recovered from the culture medium by a batch process. Insome embodiments the secreted nutritive polypeptide is recovered fromthe culture medium by a semi-continuous process. In some embodiments thesecreted nutritive polypeptide is recovered from the culture medium by afed-batch process. Those skilled in the art are aware of many suitablemethods available for culturing recombinant cells to produce (andoptionally secrete) a recombinant nutritive polypeptide as disclosedherein, as well as for purification and/or isolation of expressedrecombinant polypeptides. The methods chosen for polypeptidepurification depend on many variables, including the properties of thepolypeptide of interest. Various methods of purification are known inthe art including diafilitration, precipitation, and chromatography.

Non-Secreted

In some aspects, proteins can be isolated in the absence of secretion.For example, a cell having the protein (e.g., on the cell surface orintracellularly) can be lysed and the protein can be purified usingstandard methods such as chromatography or antibody-based isolation ofthe protein from the lysate. In some aspects, a cell surface expressedprotein can be enzymatically cleaved from the surface.

Isolation of Nutritive Polypeptides from Biological Materials fromEdible Species

In some embodiments a nutritive polypeptide having a desired amino acidor plurality of amino acids, which are optionally present in a desiredamino acid sequence, is isolated or purified from a food source, or froma biological material from an edible species. For example, a biologicalmaterial of a plant includes nuts, seeds, leaves, and roots: abiological material of a mammal includes milk, muscle, sera, and liver.Isolation methods include solubilization, chromatography, andprecipitation.

Nutritive polypeptides are isolated from biological materials byspecific solubilization of the targeted nutritive polypeptide. Thebiological material is suspended and homogenized in a solubilizationsolution. The solubilization solution is selected based on the nutritivepolypeptides physiochemical properties. Composition of thesolubilization solution is a mixture of water, detergent, salt, pH,chaotrope, cosmotrope, and/or organic solvent. As an example, proteinshigh in proline are known to be soluble in ethanol solutions (Dickey, L.C., et al. Industrial Crops and Products 10.2 (1999): 137-143.). Anutritive polypeptide with high proline content is selected and isolatedby suspending the biological material in ethanol at a ratio (w/w) ofliquid to biological material of 1:1, 2:1, 3:1, 4:1 or other ratiorecognized in the art. The suspension is blended and insoluble materialis removed by centrifugation. The ethanol soluble nutritive polypeptideis purified solubly in the ethanol fraction.

Nutritive polypeptides are isolated from biological materials byprecipitation of the targeted nutritive polypeptide or precipitation ofother proteins. Precipitating agents include salt, pH, heat,flocculants, chaotropes, cosmotropes, and organic solvents. The mode ofprecipitation is selected for a given nutritive polypeptide based on theproteins physiochemical properties. As an example, a nutritivepolypeptide is selected to be thermal stable at pH 7 by low solvationscore and low aggregation score as described herein. To purify thisprotein the biological material is suspended in a neutral pH aqueoussolution and homogenized. Insoluble material is removed from solution bycentrifugation. To purify the nutritive polypeptide from other proteins,the supernatant is heated to 90 degrees C. for 10 minutes. Insolublematerial is removed by centrifugation. Small molecules are removed fromthe supernatant by dialyzing using a 3 kDa membrane, resulting in purenutritive polypeptide.

Nutritive polypeptides are isolated from biological materials by variouschromatographic methods. The mode of chromatography selected for usedepends on the physicochemical properties of the target nutritivepolypeptide. Charged nutritive polypeptides bind to ion exchangechromatography resin through electrostatic interactions. Hydrophobicnutritive polypeptides bind to hydrophobic interaction chromatographyresin through hydrophobic association. Mixed-mode chromatography can beused for a variety of nutritive polypeptides, and can act through avariety of interactions. Metal affinity chromatography can be used fornutritive polypeptides that bind to metal ions. As an example, anutritive polypeptide is selected to have a high charge per amino acidat pH 4 so that it binds tightly to a cation-exchange resin. Thebiological material is added to a low ionic strength pH 4 aqueoussolution and homogenized. Insoluble material is removed bycentrifugation. The soluble material is added to a cation exchangeresin, such as POROS® XS Strong Cation Exchange Resin from LifeTechnologies, and washed with a low ionic strength pH4 solution. Thenutritive polypeptide is eluted from the resin by adding high ionicstrength (eg. 500 mM NaCl) pH 4 solution, resulting in purifiednutritive polypeptide.

Synthetic Nutritive Polypeptide Amino Acid Compositions

In some embodiments compositions of this disclosure contain a pluralityof free amino acids that represents the molar ratio of the plurality ofamino acids present in a selected nutritive polypeptide., herein termeda “nutritive polypeptide blend”. The compositions in certain embodimentsinclude both free amino acids and nutritive polypeptides. As used hereinin these embodiments, disclosure of a nutritive polypeptide andcompositions and formulations containing the nutritive polypeptideincludes disclosure of a nutritive polypeptide blend and compositionsand formulations containing the nutritive polypeptide blend, as well asa composition in which a first amount of amino acids are present in theform of a nutritive polypeptide and a second amount of amino acids arepresent in free amino acid form.

Synthetic Methods of Production

In some embodiments proteins of this disclosure are synthesizedchemically without the use of a recombinant production system. Proteinsynthesis can be carried out in a liquid-phase system or in asolid-phase system using techniques known in the art (see, e.g.,Atherton, E., Sheppard. R. C. (1989). Solid Phase peptide synthesis: apractical approach. Oxford. England: IRL Press; Stewart, J. M., Young.J. D. (1984). Solid phase peptide synthesis (2nd ed.). Rockford: PierceChemical Company.

Peptide chemistry and synthetic methods are well known in the art and aprotein of this disclosure can be made using any method known in theart. A non-limiting example of such a method is the synthesis of aresin-bound peptide (including methods for deprotection of amino acids,methods for cleaving the peptide from the resin, and for itspurification).

For example, Fmoc-protected amino acid derivatives that can be used tosynthesize the peptides are the standard recommended: Fmoc-Ala-OH,Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH,Fmoc-Gln(Trt)-OH. Fmoc-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH,Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(BOC)-OH, Fmoc-Met-OH, Fmoc-Phe-OH,Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(BOC)-OH,Fmoc-Tyr(tBu)-OH and Fmoc-Val-OH (supplied from, e.g., Anaspec, Bachem.Iris Biotech, or NovabioChem). Resin bound peptide synthesis isperformed, for example, using Fmoc based chemistry on a Prelude SolidPhase Peptide Synthesizer from Protein Technologies (Tucson, Ariz. 85714U.S.A.). A suitable resin for the preparation of C-terminal carboxylicacids is a pre-loaded, low-load Wang resin available from NovabioChem(e.g. low load fmoc-Thr(tBu)-Wang resin, LL, 0.27 mmol/g). A suitableresin for the synthesis of peptides with a C-terminal amide isPAL-ChemMatrix resin available from Matrix-Innovation. The N-terminalalpha amino group is protected with Boc.

Fmoc-deprotection can be achieved with 20% piperidine in NMP for 2×3min. The coupling chemistry is DIC/HOAt/collidine in NMP. Aminoacid/HOAt solutions (0.3 M/0.3 M in NMP at a molar excess of 3-10 fold)are added to the resin followed by the same molar equivalent of DIC (3 Min NMP) followed by collidine (3 M in NMP). For example, the followingamounts of 0.3 M amino acid/HOAt solution are used per coupling for thefollowing scale reactions: Scale/ml, 0.05 mmol/1.5 mL, 0.10 mmol/3.0 mL,0.25 mmol/7.5 mL. Coupling time is either 2×30 min or 1×240 min. Aftersynthesis the resin is washed with DCM, and the peptide is cleaved fromthe resin by a 2-3 hour treatment with TFA/TIS/water (95/2.5/2.5)followed by precipitation with diethylether. The precipitate is washedwith diethylether. The crude peptide is dissolved in a suitable mixtureof water and MeCN such as water/MeCN (4:1) and purified byreversed-phase preparative HPLC (Waters Deltaprep 4000 or Gilson) on acolumn containing C18-silica gel. Elution is performed with anincreasing gradient of MeCN in water containing 0.1% TFA. Relevantfractions are checked by analytical HPLC or UPLC. Fractions containingthe pure target peptide are mixed and concentrated under reducedpressure. The resulting solution is analyzed (HPLC, LCMS) and theproduct is quantified using a chemiluminescent nitrogen specific HPLCdetector (Antek 8060 HPLC-CLND) or by measuring UV-absorption at 280 nm.The product is dispensed into glass vials. The vials are capped withMillipore glassfibre prefilters. Freeze-drying affords the peptidetrifluoroacetate as a white solid. The resulting peptides can bedetected and characterized using LCMS and/or UPLC, for example, usingstandard methods known in the art. LCMS can be performed on a setupconsisting of Waters Acquity UPLC system and LCT Premier XE massspectrometer from Micromass. The UPLC pump is connected to two eluentreservoirs containing: A) 0.1% Formic acid in water; and B) 0.1% Formicacid in acetonitrile. The analysis is performed at RT by injecting anappropriate volume of the sample (preferably 2-10 μl) onto the columnwhich is eluted with a gradient of A and B. The UPLC conditions,detector settings and mass spectrometer settings are: Column: WatersAcquity UPLC BEH, C-18, 1.7 μm, 2.1 mm×50 mm. Gradient: Linear 5%-95%acetonitrile during 4.0 min (alternatively 8.0 min) at 0.4 ml/min.Detection: 214 nm (analogue output from TUV (Tunable UV detector)). MSionisation mode: API-ES Scan: 100-2000 amu (alternatively 500-2000 amu),step 0.1 amu. UPLC methods are well known. Non-limiting examples ofmethods that can be used are described at pages 16-17 of US 2013/0053310A1, published Feb. 28, 2013, for example.

Inactivating Enzyme Activity

In some aspects, a protein is an enzyme or has enzymatic activity. Insome aspects, it can be desirable to inactivate or reduce the enzymaticactivity of the enzyme. Various methods are known in the art for enzymeinactivation including application of heat, application of one or moredetergents, application of one or more metal chelators, reduction,oxidation, application of one or more chaotropes, covalent modification,alternating post translational modifications, e.g., via enzymatic orchemical alteration, altering pH (acidic and basic), or altering thesalt concentration. For example, heat inactivation is typicallyperformed at a certain temperature for a certain amount of time, e.g.,most endonucleases are inactivated by incubation at 65° C. for 20minutes. In some aspects, enzymes can be mutated to eliminate or reduceenzymatic activity. e.g., by causing the enzyme to misfold. In addition,high pressure carbon dioxide (HPCD) has been demonstrated to aneffective non-thermal processing technique for inactivating enzymes. SeeHu et al., Enzyme Inactivation in Food Processing using High PressureCarbon Dioxide Technology; Critical Review in Food Science andNutrition; Volume 52, Issue 2, 2013. Various other forms of enzymeinactivation are known in the art, the parameters of which can beadjusted as needed to alter enzyme activity accordingly. Various methodsfor enzyme inactivation and excipients such as oxidation. e.g., bleach,H₂O₂, and ethylene oxide; to reduce disulphides, e.g., DTT, BME, andTCEP: high pH using Na₂CO₃, Tris Base, or Na₂HPO₄; low pH using CitricAcid. Boric Acid, Acetic Acid, or Tris HCl; Heat using temperatures 30°C.-100° C. over a period of time; protein unfolding with chaotropes suchas Thiocyanate, Urea, Guanidine HCl, or CaCl₂; protein unfold withsurfactants (e.g., detergents) such as MPD, Triton (non-ionic), CHAPS(zwitterionic), or Tween (non-ionic), or to chelate metals with EDTA orCitrate.

Cell Proliferation Assays

Cell proliferation assays can be used to measure the relative importanceof a protein or portion thereof to the proliferative process. In someaspects, cell proliferation can be measured under starvation conditionsin the presence or absence of a protein or interest. For example, cellscan be starved over a period of time (e.g., 48 hours) with a mediumhaving or lacking each, respective protein of interest in a tissueculture incubator. After the incubation, a detection agent such asAlamarBlue can be added and fluorescence measured as an output forproliferation. In some aspects, cell proliferation can be measured aspart of a dose response to a protein of interest. For example, cells canbe starved in medium having or lacking each, respective protein ofinterest in a tissue culture incubator. After starvation, the cells canthen be treated with varying concentrations of the protein (e.g., 0, 20,100, or 1000 μM) that was lacking in the initial culture in the same,source medium lacking the respective protein. The cells can then beincubated again in a for tissue culture incubator. After the incubationa detection agent such as AlamarBlue can be added and fluorescence read.

Allergenicity Assays

For some embodiments it is preferred that the protein not exhibitinappropriately high allergenicity. Accordingly, in some embodiments thepotential allergenicy of the protein is assessed. This can be done byany suitable method known in the art. In some embodiments anallergenicity score is calculated. The allergenicity score is a primarysequence based metric based on WHO recommendations(fao.org/ag/agn/food/pd/allergygm.pdf) for assessing how similar aprotein is to any known allergen, the primary prediction being that highpercent identity between a target and a known allergen is likelyindicative of cross reactivity. For a given protein, the likelihood ofeliciting an allergic response can be assessed via one or both of acomplimentary pair of sequence homology based tests. The first testdetermines the protein's percent identity across the entire sequence viaa global-global sequence alignment to a database of known allergensusing the FASTA algorithm with the BLOSUM50 substitution matrix, a gapopen penalty of 10, and a gap extension penalty of 2. It has beensuggested that proteins with less than 50% global homology are unlikelyto be allergenic (Goodman R. E. et al. Allergenicity assessment ofgenetically modified crops-what makes sense? Nat. Biotech. 26, 73-81(2008); Aalberse R. C. Structural biology of allergens. J. Allergy Clin.Immunol. 106, 228-238 (2000)).

In some embodiments of a protein, the protein has less than 50% globalhomology to any known allergen in the database used for the analysis. Insome embodiments a cutoff of less than 40% homology is used. In someembodiments a cutoff of less than 30% homology is used. In someembodiments a cutoff of less than 20% homology is used. In someembodiments a cutoff of less than 10% homology is used. In someembodiments a cutoff of from 40% to 50% is used. In some embodiments acutoff of from 30% to 50% is used. In some embodiments a cutoff of from20% to 50% is used. In some embodiments a cutoff of from 10% to 50% isused. In some embodiments a cutoff of from 5% to 50% is used. In someembodiments a cutoff of from 0% to 50% is used. In some embodiments acutoff of greater than 50% global homology to any known allergen in thedatabase used for the analysis is used. In some embodiments a cutoff offrom 50% to 60% is used. In some embodiments a cutoff of from 50% to 70%is used. In some embodiments a cutoff of from 50% to 80% is used. Insome embodiments a cutoff of from 50% to 90% is used. In someembodiments a cutoff of from 55% to 60% is used. In some embodiments acutoff of from 65% to 70% is used. In some embodiments a cutoff of from70% to 75% is used. In some embodiments a cutoff of from 75% to 80% isused.

The second test assesses the local allergenicity along the proteinsequence by determining the local allergenicity of all possiblecontiguous 80 amino acid fragments via a global-local sequence alignmentof each fragment to a database of known allergens using the FASTAalgorithm with the BLOSUM50 substitution matrix, a gap open penalty of10, and a gap extension penalty of 2. The highest percent identity ofany 80 amino acid window with any allergen is taken as the final scorefor the protein of interest. The WHO guidelines suggest using a 35%identity cutoff with this fragment test. In some embodiments of aprotein, all possible fragments of the protein have less than 35% localhomology to any known allergen in the database used for the analysisusing this test. In some embodiments a cutoff of less than 30% homologyis used. In some embodiments a cutoff of from 30% to 35% homology isused. In some embodiments a cutoff of from 25% to 30% homology is used.In some embodiments a cutoff of from 20% to 25% homology is used. Insome embodiments a cutoff of from 15% to 20% homology is used. In someembodiments a cutoff of from 10% to 15% homology is used. In someembodiments a cutoff of from 5% to 10% homology is used. In someembodiments a cutoff of from 0% to 5% homology is used. In someembodiments a cutoff of greater than 35% homology is used. In someembodiments a cutoff of from 35% to 40% homology is used. In someembodiments a cutoff of from 40% to 45% homology is used. In someembodiments a cutoff of from 45% to 50% homology is used. In someembodiments a cutoff of from 50% to 55% homology is used. In someembodiments a cutoff of from 55% to 60% homology is used. In someembodiments a cutoff of from 65% to 70% homology is used. In someembodiments a cutoff of from 70% to 75% homology is used. In someembodiments a cutoff of from 75% to 80% homology is used.

Skilled artisans are able to identify and use a suitable database ofknown allergens for this purpose. In some embodiments the database iscustom made by selecting proteins from more than one database source. Insome embodiments the custom database comprises pooled allergen listscollected by the Food Allergy Research and Resource Program(allergenonline.org/), UNIPROT annotations (uniprot.org/docs/allergen),and the Structural Database of Allergenic Proteins (SDAP,fermi.utmb.edu/SDAP/sdap_lnk.html). This database includes all currentlyrecognized allergens by the International Union of ImmunologicalSocieties (IUIS, allergen.org/) as well as a large number of additionalallergens not yet officially named. In some embodiments the databasecomprises a subset of known allergen proteins available in knowndatabases; that is, the database is a custom selected subset of knownallergen proteins. In some embodiments the database of known allergenscomprises at least 10 proteins, at least 20 proteins, at least 30proteins, at least 40 proteins, at least 50 proteins, at least 100,proteins, at least 200 proteins, at least 300 proteins, at least 400proteins, at least 500 proteins, at least 600 proteins, at least 700proteins, at least 800 proteins, at least 900 proteins, at least 1,000proteins, at least 1,100 proteins, at least 1,200 proteins, at least1,300 proteins, at least 1,400 proteins, at least 1,500 proteins, atleast 1,600 proteins, at least 1,700 proteins, at least 1,800 proteins,at least 1,900 proteins, or at least 2.000 proteins. In some embodimentsthe database of known allergens comprises from 100 to 500 proteins, from200 to 1,000 proteins, from 500 to 1,000 proteins, from 500 to 1,000proteins, or from 1,000 to 2,000 proteins.

In some embodiments all (or a selected subset) of contiguous amino acidwindows of different lengths (e.g., 70, 60, 50, 40, 30, 20, 10, 8 or 6amino acid windows) of a protein are tested against the allergendatabase and peptide sequences that have 100% identity, 95% or higheridentity, 90% or higher identity, 85% or higher identity, 80% or higheridentity, 75% or higher identity, 70% or higher identity, 65% or higheridentity, 60% or higher identity, 55% or higher identity, or 50% orhigher identity matches are identified for further examination ofpotential allergenicity.

Another method of predicting the allergenicity of a protein is to assessthe homology of the protein to a protein of human origin. The humanimmune system is exposed to a multitude of possible allergenic proteinson a regular basis and has the intrinsic ability to differentiatebetween the host body's proteins and exogenous proteins. The exactnature of this ability is not always clear, and there are many diseasesthat arise as a result of the failure of the body to differentiate selffrom non-self (e.g., arthritis). Nonetheless, the fundamental analysisis that proteins that share a degree of sequence homology to humanproteins are less likely to elicit an immune response. In particular, ithas been shown that for some protein families with known allergenicmembers (tropomyosins, parvalbumins, caseins), those proteins that bearmore sequence homology to their human counterparts relative to knownallergenic proteins, are not thought to be allergenic (Jenkins J. A. etal. Evolutionary distance from human homologs reflects allergenicity ofanimal food proteins. J. Allergy Clin Immunol. 120 (2007): 1399-1405).For a given protein, a human homology score is measured by determiningthe maximum percent identity of the protein to a database of humanproteins (e.g., the UNIPROT database) from a global-local alignmentusing the FASTA algorithm with the BLOSUM50 substitution matrix, a gapopen penalty of 10, and a gap extension penalty of 2. According toJenkins et al. (Jenkins J. A. et al. Evolutionary distance from humanhomologs reflects allergenicity of animal food proteins J. Allergy ClinImmunol. 120 (2007): 1399-1405) proteins with a sequence identity to ahuman protein above about 62% are less likely to be allergenic. Skilledartisans are able to identify and use a suitable database of known humanproteins for this purpose, for example, by searching the UNIPROTdatabase (uniprot.org). In some embodiments the database is custom madeby selecting proteins from more than one database source. Of course thedatabase may but need not be comprehensive. In some embodiments thedatabase comprises a subset of human proteins: that is, the database isa custom selected subset of human proteins. In some embodiments thedatabase of human proteins comprises at least 10 proteins, at least 20proteins, at least 30 proteins, at least 40 proteins, at least 50proteins, at least 100, proteins, at least 200 proteins, at least 300proteins, at least 400 proteins, at least 500 proteins, at least 600proteins, at least 700 proteins, at least 800 proteins, at least 900proteins, at least 1,000 proteins, at least 2,000 proteins, at least3,000 proteins, at least 4.000 proteins, at least 5,000 proteins, atleast 6,000 proteins, at least 7,000 proteins, at least 8,000 proteins,at least 9,000 proteins, or at least 10,000 proteins. In someembodiments the database comprises from 100 to 500 proteins, from 200 to1,000 proteins, from 500 to 1,000 proteins, from 500 to 1,000 proteins,from 1,000 to 2.000 proteins, from 1,000 to 5,000 proteins, or from5.000 to 10.000 proteins. In some embodiments the database comprises atleast 90%, at least 95%, or at least 99% of all known human proteins.

In some embodiments of a protein, the protein is at least 20% homologousto a human protein. In some embodiments a cutoff of at least 30%homology is used. In some embodiments a cutoff of at least 40% homologyis used. In some embodiments a cutoff of at least 50% homology is used.In some embodiments a cutoff of at least 60% homology is used. In someembodiments a cutoff of at least 70% homology is used. In someembodiments a cutoff of at least 80% homology is used. In someembodiments a cutoff of at least 62% homology is used. In someembodiments a cutoff of from at least 20% homology to at least 30%homology is used. In some embodiments a cutoff of from at least 30%homology to at least 40% homology is used. In some embodiments a cutoffof from at least 50% homology to at least 60% homology is used. In someembodiments a cutoff of from at least 60% homology to at least 70%homology is used. In some embodiments a cutoff of from at least 70%homology to at least 80% homology is used.

Thermostability Assays

As used herein, a “stable” protein is one that resists changes (e.g.,unfolding, oxidation, aggregation, hydrolysis, etc.) that alter thebiophysical (e.g., solubility), biological (e.g., digestibility), orcompositional (e.g. proportion of Leucine amino acids) traits of theprotein of interest.

Protein stability can be measured using various assays known in the artand proteins disclosed herein and having stability above a threshold canbe selected. In some embodiments a protein is selected that displaysthermal stability that is comparable to or better than that of wheyprotein. Thermal stability is a property that can help predict the shelflife of a protein. In some embodiments of the assay stability of proteinsamples is determined by monitoring aggregation formation using sizeexclusion chromatography (SEC) after exposure to extreme temperatures.Aqueous samples of the protein to be tested are placed in a heatingblock at 90° C. and samples are taken after 0, 1, 5, 10, 30 and 60 minfor SEC analysis. Protein is detected by monitoring absorbance at 214nm, and aggregates are characterized as peaks eluting faster than theprotein of interest. No overall change in peak area indicates noprecipitation of protein during the heat treatment. Whey protein hasbeen shown to rapidly form ˜80% aggregates when exposed to 90° C. insuch an assay.

In some embodiments the thermal stability of a protein is determined byheating a sample slowly from 25° C. to 95° C. in presence of ahydrophobic dye (e.g., ProteoStat® Thermal shift stability assay kit,Enzo Life Sciences) that binds to aggregated proteins that are formed asthe protein denatures with increasing temperature (Niesen, F. H.,Berglund, H. & Vadadi, M., 2007. The use of differential scanningfluorimetry to detect ligand interactions that promote proteinstability. Nature Protocols, Volume 2, pp. 2212-2221). Upon binding, thedye's fluorescence increases significantly, which is recorded by anrtPCR instrument and represented as the protein's melting curve(Lavinder. J. J., Hari, S. B., Suillivan, B. J. & Magilery, T. J., 2009.High-Throughput Thermal Scanning: A General, Rapid Dye-Binding ThermalShift Screen for Protein Engineering. Journal of the American ChemicalSociety, pp. 3794-3795). After the thermal shift is complete, samplesare examined for insoluble precipitates and further analyzed byanalytical size exclusion chromatography (SEC).

Solubility Assays

In some embodiments of the proteins disclosed herein the protein issoluble. Solubility can be measured by any method known in the art. Insome embodiments solubility is examined by centrifuge concentrationfollowed by protein concentration assays. Samples of proteins in 20 mMHEPES pH 7.5 are tested for protein concentration according to protocolsusing two methods, Coomassie Plus (Bradford) Protein Assay (ThermoScientific) and Bicinchoninic Acid (BCA) Protein Assay (SigmadAldrich).Based on these measurements 10 mg of protein is added to an Amicon Ultra3 kDa centrifugal filter (Millipore). Samples are concentrated bycentrifugation at 10,000×g for 30 minutes. The final, now concentrated,samples are examined for precipitated protein and then tested forprotein concentration as above using two methods, Bradford and BCA.

In some embodiments the proteins have a final solubility limit of atleast 5 g/L, 10 g/L, 20 g/L, 30 g/L, 40 g/L, 50 g/L, or 100 g/L atphysiological pH. In some embodiments the proteins are greater than 50%,greater than 60%, greater than 70%, greater than 80%, greater than 90%,greater than 95%, greater than 96%, greater than 97%, greater than 98%,greater than 99%, or greater than 99.5% soluble with no precipitatedprotein observed at a concentration of greater than 5 g/L, or 10 g/L, or20 g/L, or 30 g/L, or 40 g/L, or 50 g/L, or 100 g/L at physiological pH.In some embodiments, the solubility of the protein is higher than thosetypically reported in studies examining the solubility limits of whey(12.5 g/L; Pelegrine et al., Lebensm.-Wiss. U.-Technol. 38 (2005) 77-80)and soy (10 g/L; Lee et al., JAOCS 80(1) (2003) 85-90).

Eukaryotic proteins are often glycosylated, and the carbohydrate chainsthat are attached to proteins serve various functions. N-linked andO-linked glycosylation are the two most common forms of glycosylationoccurring in proteins. N-linked glycosylation is the attachment of asugar molecule to a nitrogen atom in an amino acid residue in a protein.N-linked glycosylation occurs at Asparagine and Arginine residues.O-linked glycosylation is the attachment of a sugar molecule to anoxygen atom in an amino acid residue in a protein. O-linkedglycosylation occurs at Threonine and Serine residues.

Glycosylated proteins are often more soluble than their un-glycosylatedforms. In terms of protein drugs, proper glycosylation usually confershigh activity, proper antigen binding, better stability in the blood,etc. However, glycosylation necessarily means that a protein “carrieswith it” sugar moieties. Such sugar moieties may reduce the usefulnessof the proteins of this disclosure including recombinant proteins. Forexample, as demonstrated in the examples, a comparison of digestion ofglycosylated and non-glycosylated forms of the same proteins shows thatthe non-glycosylated forms are digested more quickly than theglycosylated forms. For these reasons, in some embodiments the nutritiveproteins according to the disclosure comprise low or no glycosylation.For example, in some embodiments the proteins comprise a ratio ofnon-glycosidated to total amino acid residues of at least 80%, at least85%, at least 90%, at least 95%, at least 96%, at least 97%, at least98%, or at least 99%. In some embodiments the proteins to not compriseany glycosylation.

In some embodiments, the protein according to the disclosure isdeglycosylated after it is produced or after it is isolated. Proteins oflow or no glycosylation can be made by any method known in the art. Forexample, enzymatic and/or chemical methods can be used (Biochem. J.(2003) 376, p339-350.). Enzymes are produced commercially at researchscales for the removal of N-linked and O-linked oligosaccharides.Chemical methods include use of trifluoromethanesulfonic acid toselectively break N-linked and O-linked peptide-saccharide bonds. Thismethod often results in a more complete deglycosylation than does theuse of enzymatic methods.

In other embodiments, the protein according to the disclosure isproduced with low or no glycosylation by a host organism. Most bacteriaand other prokaryotes have very limited capabilities to glycosylateproteins, especially heterologous proteins. Accordingly, in someembodiments of this disclosure a protein is made recombinantly in amicroorganism such that the level of glycosylation of the recombinantprotein is low or no glycosylation. In some embodiments the level ofglycosylation of the recombinant protein is lower than the level ofglycosylation of the protein as it occurs in the organism from which itis derived. Glycosylation of a protein can vary based on the hostorganism, in other words some hosts will produce more glycosylationrelative to one or more other hosts; while other hosts will produce lessg glycosylation relative to one or more other hosts. Differences in theamount of glycosylation can be measured based upon, e.g., the mass ofglycosylation present and/or the total number of glycosylation sitespresent.

Toxicity and Anti-Nutricity Assays

For most embodiments it is preferred that the protein not exhibitinappropriately high toxicity. Accordingly, in some embodiments thepotential toxicity of the protein is assessed. This can be done by anysuitable method known in the art. In some embodiments a toxicity scoreis calculated by determining the protein's percent identity to databasesof known toxic proteins (e.g., toxic proteins identified from theUNIPROT database). A global-global alignment of the protein of interestagainst the database of known toxins is performed using the FASTAalgorithm with the BLOSUM50 substitution matrix, a gap open penalty of10, and a gap extension penalty of 2. In some embodiments of a protein,the protein is less than 35% homologous to a known toxin. In someembodiments a cutoff of less than 35% homology is used. In someembodiments a cutoff of from 30% to 35% homology is used. In someembodiments a cutoff of from 25% to 35% homology is used. In someembodiments a cutoff of from 20% to 35% homology is used. In someembodiments a cutoff of from 15% to 35% homology is used. In someembodiments a cutoff of from 10% to 35% homology is used. In someembodiments a cutoff of from 5% to 35% homology is used. In someembodiments a cutoff of from 0% to 35% homology is used. In someembodiments a cutoff of grater than 35% homology is used. In someembodiments a cutoff of from 35% to 40% homology is used. In someembodiments a cutoff of from 35% to 45% homology is used. In someembodiments a cutoff of from 35% to 50% homology is used. In someembodiments a cutoff of from 35% to 55% homology is used. In someembodiments a cutoff of from 35% to 60% homology is used. In someembodiments a cutoff of from 35% to 70% homology is used. In someembodiments a cutoff of from 35% to 75% homology is used. In someembodiments a cutoff of from 35% to 80% homology is used. Skilledartisans are able to identify and use a suitable database of knowntoxins for this purpose, for example, by searching the UNIPROT database(uniprot.org). In some embodiments the database is custom made byselecting proteins identified as toxins from more than one databasesource. In some embodiments the database comprises a subset of knowntoxic proteins; that is, the database is a custom selected subset ofknown toxic proteins. In some embodiments the database of toxic proteinscomprises at least 10 proteins, at least 20 proteins, at least 30proteins, at least 40 proteins, at least 50 proteins, at least 100,proteins, at least 200 proteins, at least 300 proteins, at least 400proteins, at least 500 proteins, at least 600 proteins, at least 700proteins, at least 800 proteins, at least 900 proteins, at least 1,000proteins, at least 2.000 proteins, at least 3,000 proteins, at least4,000 proteins, at least 5,000 proteins, at least 6,000 proteins, atleast 7,000 proteins, at least 8,000 proteins, at least 9,000 proteins,or at least 10,000 proteins. In some embodiments the database comprisesfrom 100 to 500 proteins, from 200 to 1,000 proteins, from 500 to 1,000proteins, from 500 to 1,000 proteins, from 1,000 to 2,000 proteins, from1,000 to 5,000 proteins, or from 5,000 to 10,000 proteins.

Anti-Nutricity and Anti-Nutrients

For some embodiments it is preferred that the protein not exhibitanti-nutritional activity (“anti-nutricity”), i.e., proteins that havethe potential to prevent the absorption of nutrients from food. Examplesof anti-nutritive sequences causing such anti-nutricity include proteaseinhibitors, which inhibit the actions of trypsin, pepsin and otherproteases in the gut, preventing the digestion and subsequent absorptionof protein.

Disclosed herein are formulations containing isolated nutritivepolypeptides that are substantially free of anti-nutritive sequences. Insome embodiments the nutritive polypeptide has an anti-nutritivesimilarity score below about 1, below about 0.5, or below about 0.1. Thenutritive polypeptide is present in the formulation in an amount greaterthan about 10 g, and the formulation is substantially free ofanti-nutritive factors. The formulation is present as a liquid,semi-liquid or gel in a volume not greater than about 500 ml or as asolid or semi-solid in a mass not greater than about 200 g. Thenutritive polypeptide may have low homology with a protease inhibitor,such as a member of the serpin family of polypeptides, e.g., it is lessthan 90%, identical, or is less than 85%, 80%, 75%, 70%, 65%, 60%, 55%,50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or less than 5%identical.

Accordingly, in some embodiments the potential anti-nutricity of theprotein is assessed. This can be done by any suitable method known inthe art. In some embodiments an anti-nutricity score is calculated bydetermining the protein's percent identity to databases of knownprotease inhibitors (e.g., protease inhibitors identified from theUNIPROT database). A global-global alignment of the protein of interestagainst the database of known protease inhibitors is performed using theFASTA algorithm with the BLOSUM50 substitution matrix, a gap openpenalty of 10, and a gap extension penalty of 2, to identify whether theprotein is homologous to a known anti-protein. In some embodiments of aprotein, the protein has less than 35% global homology to any knownanti-protein (e.g., any known protease inhibitor) in the database usedfor the analysis. In some embodiments a cutoff of less than 35% identifyis used. In some embodiments a cutoff of from 30% to 35% is used. Insome embodiments a cutoff of from 25% to 35% is used. In someembodiments a cutoff of from 20% to 35% is used. In some embodiments acutoff of from 15% to 35% is used. In some embodiments a cutoff of from10% to 35% is used. In some embodiments a cutoff of from 5% to 35% isused. In some embodiments a cutoff of from 0% to 35% is used. In someembodiments a cutoff of greater than 35% identify is used. In someembodiments a cutoff of from 35% to 40% is used. In some embodiments acutoff of from 35% to 45% is used. In some embodiments a cutoff of from35% to 50% is used. In some embodiments a cutoff of from 35% to 55% isused. In some embodiments a cutoff of from 35% to 60% is used. In someembodiments a cutoff of from 35% to 70% is used. In some embodiments acutoff of from 35% to 75% is used. In some embodiments a cutoff of from35% to 80% is used. Skilled artisans are able to identify and use asuitable database of known protease inhibitors for this purpose, forexample, by searching the UNIPROT database (uniprot.org). In someembodiments the database is custom made by selecting proteins identifiedprotease-inhibitors as from more than one database source. In someembodiments the database comprises a subset of known protease inhibitorsavailable in databases; that is, the database is a custom selectedsubset of known protease inhibitor proteins. In some embodiments thedatabase of known protease inhibitor proteins comprises at least 10proteins, at least 20 proteins, at least 30 proteins, at least 40proteins, at least 50 proteins, at least 100, proteins, at least 200proteins, at least 300 proteins, at least 400 proteins, at least 500proteins, at least 600 proteins, at least 700 proteins, at least 800proteins, at least 900 proteins, at least 1,000 proteins, at least 1,100proteins, at least 1,200 proteins, at least 1,300 proteins, at least1,400 proteins, at least 1,500 proteins, at least 1.600 proteins, atleast 1,700 proteins, at least 1,800 proteins, at least 1,900 proteins,or at least 2,000 proteins. In some embodiments the database of knownprotease inhibitor proteins comprises from 100 to 500 proteins, from 200to 1,000 proteins, from 500 to 1,000 proteins, from 500 to 1,000proteins, or from 1,000 to 2,000 proteins, or from 2,000 to 3,000proteins.

In other embodiments a protein that does exhibit some degree of proteaseinhibitor activity is used. For example, in some embodiments such aprotein can be useful because it delays protease digestion when thenutritive protein is consumed such that the protein traverse a greaterdistance within the GI tract before it is digested, thus delayingabsorption. For example, in some embodiments the protein inhibitsgastric digestion but not intestinal digestion. Delaney B. et al.(Evaluation of protein safety in the context of agriculturalbiotechnology. Food. Chem. Toxicol. 46 (2008: S71-S97)) suggests thatone should avoid both known toxic and anti-proteins when assessing thesafety of a possible food protein. In some embodiments of a protein, theprotein has a favorably low level of global homology to a database ofknown toxic proteins and/or a favorably low level of global homology toa database of known anti-nutricity proteins (e.g., protease inhibitors),as defined herein.

Antinutrients.

Provided are nutritional compositions that lack anti-nutrients (orantinutrients). Antinutrients are compounds, usually other thanproteins, which are typically found in plant foods and have been foundto have both adverse effects and, in some situations, certain healthbenefits. For instance, phytic acid, lectins, phenolic compounds,saponins, and enzyme inhibitors have been shown to reduce theavailability of nutrients and to cause the inhibition of growth, andphytoestrogens and lignans have been linked with infertility problems.On the other hand, phytic acid, lectins, phenolic compounds, amylaseinhibitors, and saponins have been shown to reduce the blood glucose andinsulin response to starch foods and/or the plasma cholesterol andtriglycerides. Furthermore, phytic acid, phenolics, saponins, proteaseinhibitors, phytoestrogens, and lignans have been linked to reducedcancer risks.

Provided are methods for reducing the amount anti-nutritional factors ina food product, by treating the food product with a thermal treatmentcomprising steam or hot air having a temperature greater than about 90degrees C. for at least 1 minute, combining with the treated foodproduct with a composition containing an isolated nutritive polypeptide.Optionally, the step of thermal treatment degrades at least oneanti-nutritional factor such as a saponin, a lectin, and a prolamin, aprotease inhibitor, or phytic acid.

Anti-nutritional factors are detected in a protein composition asfollows. Phytic acid: The procedure of Wheeler and Ferrel (Wheeler, E.L., Ferrel, R. E., Cereal Chem. 1971, 48, 312) is used for thedetermination of phytic acid extracted in 3% trichloroacetic acid.Raffinose family oligosaccharides: Protein samples are extracted with70% ethanol using Soxhlet apparatus for 6-8 h and thin-layerchromatography is used for the quantitative determination of raffinoseand stachyose in the extract according to the procedure of Tanaka et al.(Tanaka, M., Thananunkul, D., Lee. T. C., Chichester, C. O., J. FoodSci. 1975, 40, 1087-1088). Trypsin inhibitor. The method of Kakade etal. (Kakade, M. L., Rackis, J. J., McGhee, J. E., Puski, G., CerealChem. 1974, 51, 376-82) is used for determining the trypsin inhibitoractivity in raw and treated samples. One trypsin inhibitor unit (TIU) isdefined as a decrease in absorbance at 410 nm by 0.01 in 10 min and datawere expressed as TIU*mg-1. Amylase inhibitor. The inhibitor isextracted in 0.15 m NaCl according to the procedure of Baker et al.(Baker. J. E., Woo, S. M., Throne, J. E., Finny, P. L., Environm.Entomol. 1991, 20, 53±60) and assayed by the method of Huesing et al.(Huesing, J. E., Shade, R. E., Chrispeels, M. J., Murdok, L. L., PlantPhysiol. 1991, 96, 993±996). One amylase inhibitor unit (AIU) is definedas the amount that gives 50% inhibition of a portion of the amylase thatproduced one mg maltose monohydrate per min. Lectins: The procedure ofParedes-Lopez et al. (Paredes-Lopez, O., Schevenin, M. L., Guevara-Lara,F., Food Chem. 1989, 31, 129-137) is applied to the extraction oflectins using phosphate-buffered saline (PBS). The hemagglutininactivity (HA) of lectins in the sample extract is determined accordingto Kortt (Kortt, A. A. (Ed.), Eur. J. Biochem. 1984, 138, 519).Trypsinized human red blood cell (A, B and O) suspensions are preparedaccording to Lis and Sharon (Lis, H., Sharon, N., Methods Enzymol. 1972,28, 360±368). HA is expressed as the reciprocal of the highest dilutiongiving positive agglutination. Tannins: The tannin contents aredetermined as tannic acid by Folin-Denis reagent according to theprocedure of the AOAC (Helrich, K. (Ed.), AOAC, Official Methods ofAnalysis, Association of Official Analytical Chemists, Arlington, Va.1990)

Charge Assays and Solvation Scoring

One feature that can enhance the utility of a protein is its charge (orper amino acid charge). Proteins with higher charge can in someembodiments exhibit desirable characteristics such as increasedsolubility, increased stability, resistance to aggregation, anddesirable taste profiles. For example, a charged protein that exhibitsenhanced solubility can be formulated into a beverage or liquidformulation that includes a high concentration of protein in arelatively low volume of solution, thus delivering a large dose ofprotein nutrition per unit volume. A charged protein that exhibitsenhanced solubility can be useful, for example, in sports drinks orrecovery drinks wherein a user (e.g., an athlete) wants to ingestprotein before, during or after physical activity. A charged proteinthat exhibits enhanced solubility can also be particularly useful in aclinical setting wherein a subject (e.g., a patient or an elderlyperson) is in need of protein nutrition but is unable to ingest solidfoods or large volumes of liquids.

For example, the net charge (ChargeP) of a polypeptide at pH 7 can becalculated using the following formula:

ChargeP=−0.002−(CX(0.045)−(D)(0.999)−(EX0.998)+(H)(0.091)+(K)(1.0)+(R)(1.0)−(Y)(−0.001)

where C is the number of cysteine residues, D is the number of asparticacid residues, E is the number of glutamic acid residues. H is thenumber of histidine residues, K is the number of lysine residues. R isthe number of arginine residues and Y is the number of tyrosine residuesin the polypeptide. The per amino acid charge (ChargeA) of thepolypeptide can be calculated by dividing the net charge (ChargeP) bythe number of amino acid residues (N), i.e., ChargeA=ChargePN. (SeeBassi S (2007), “A Primer on Python for Life Science Researchers.” PLoSComput Biol 3(11): e199, doi: 10.1371/journal.pcbi.0030199).

One metric for assessing the hydrophilicity and potential solubility ofa given protein is the solvation score. Solvation score is defined asthe total free energy of solvation (i.e. the free energy changeassociated with transfer from gas phase to a dilute solution) for allamino acid side chains if each residue were solvated independently,normalized by the total number of residues in the sequence. The sidechain solvation free energies are found computationally by calculatingthe electrostatic energy difference between a vacuum dielectric of 1 anda water dielectric of 80 (by solving the Poisson-Boltzmann equation) aswell as the non-polar, Van der Waals energy using a linear solventaccessible surface area model (D. Sitkoff, K. A. Sharp, B. Honig.“Accurate Calculation of Hydration Free Energies Using MacroscopicSolvent Models”. J. Phys. Chem. 98, 1994). For amino acids withionizable sidechains (Arg, Asp, Cys, Glu, His, Lys and Tyr), an averagesolvation free energy is used based on the relative probabilities foreach ionization state at the specified pH. Solvation scores start at 0and continue into negative values, and the more negative the solvationscore, the more hydrophilic and potentially soluble the protein ispredicted to be. In some embodiments of a protein, the protein has asolvation score of −10 or less at pH 7. In some embodiments of aprotein, the protein has a solvation score of −15 or less at pH 7. Insome embodiments of a protein, the protein has a solvation score of −20or less at pH 7. In some embodiments of a protein, the protein has asolvation score of −25 or less at pH 7. In some embodiments of aprotein, the protein has a solvation score of −30 or less at pH 7. Insome embodiments of a protein, the protein has a solvation score of −35or less at pH 7. In some embodiments of a protein, the protein has asolvation score of −40 or less at pH 7.

The solvation score is a function of pH by virtue of the pH dependenceof the molar ratio of undissociated weak acid ([HA]) to conjugate base([A−]) as defined by the Henderson-Hasselbalch equation:

${pH} = {{pKa} + {\log \left( \frac{\left\lbrack A^{-} \right\rbrack}{\lbrack{HA}\rbrack} \right)}}$

All weak acids have different solvation free energies compared to theirconjugate bases, and the solvation free energy used for a given residuewhen calculating the solvation score at a given pH is the weightedaverage of those two values.

Accordingly, in some embodiments of a protein, the protein has asolvation score of −10 or less at an acidic pH. In some embodiments of aprotein, the protein has a solvation score of −15 or less at an acidicpH. In some embodiments of a protein, the protein has a solvation scoreof −20 or less at an acidic pH. In some embodiments of a protein, theprotein has a solvation score of −25 or less at an acidic pH. In someembodiments of a protein, the protein has a solvation score of −30 orless at an acidic pH. In some embodiments of a protein, the protein hasa solvation score of −35 or less at an acidic pH. In some embodiments ofa protein, the protein has a solvation score of −40 or less at acidicpH.

Accordingly, in some embodiments of a protein, the protein has asolvation score of −10 or less at a basic pH. In some embodiments of aprotein, the protein has a solvation score of −15 or less at a basic pH.In some embodiments of a protein, the protein has a solvation score of−20 or less at a basic pH. In some embodiments of a protein, the proteinhas a solvation score of −25 or less at a basic pH. In some embodimentsof a protein, the protein has a solvation score of −30 or less at abasic pH. In some embodiments of a protein, the protein has a solvationscore of −35 or less at a basic pH. In some embodiments of a protein,the protein has a solvation score of −40 or less at basic pH.

Accordingly, in some embodiments of a protein, the protein has asolvation score of −10 or less at a pH range selected from 2-3, 3-4,4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, and 11-12. In some embodiments ofa protein, the protein has a solvation score of −15 or less at a pHrange selected from 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, and11-12. In some embodiments of a protein, the protein has a solvationscore of −20 or less at a pH range selected from 2-3, 3-4, 4-5, 5-6,6-7, 7-8, 8-9, 9-10, 10-11, and 11-12. In some embodiments of a protein,the protein has a solvation score of −25 or less at a pH range selectedfrom 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, and 11-12. In someembodiments of a protein, the protein has a solvation score of −30 orless at a pH range selected from 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9,9-10, 10-11, and 11-12. In some embodiments of a protein, the proteinhas a solvation score of −35 or less at a pH range selected from 2-3,3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, and 11-12. In someembodiments of a protein, the protein has a solvation score of −40 orless at a pH range selected from 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9,9-10, 10-11, and 11-12.

Aggregation Assays and Aggregation Scoring

In some embodiments a protein of this disclosure shows resistance toaggregation, exhibiting, for example, less than 80% aggregation, 10%aggregation, or no detectable aggregation at elevated temperatures(e.g., 50° C., 60° C., 70° C., 80° C., 85° C. 90° C. or 95° C.).

One benefit of stable proteins as disclosed herein is that they can beable to be stored for an extended period of time before use, in someinstances without the need for refrigeration or cooling. In someembodiments, proteins are processed into a dry form (e.g., bylyophilization). In some embodiments, proteins are stable uponlyophilization. In some embodiments, such lyophilized proteins maintaintheir stability upon reconstitution (e.g., liquid formulation).

The aggregation score is a primary sequence based metric for assessingthe hydrophobicity and likelihood of aggregation of a given protein.Using the Kyte and Doolittle hydrophobity scale (Kyte J. Doolittle RF(May 1982) “A simple method for displaying the hydropathic character ofa protein”. J. Mol. Biol. 157 (1): 105-32), which gives hydrophobicresidues positive values and hydrophilic residues negative values, theaverage hydrophobicity of a protein sequence is calculated using amoving average of five residues. The aggregation score is drawn from theresulting plot by determining the area under the curve for valuesgreater than zero and normalizing by the total length of the protein.The underlying view is that aggregation is the result of two or morehydrophobic patches coming together to exclude water and reduce surfaceexposure, and the likelihood that a protein will aggregate is a functionof how densely packed its hydrophobic (i.e., aggregation prone) residuesare. Aggregation scores start at 0 and continue into positive values,and the smaller the aggregation score, the less hydrophobic andpotentially less prone to aggregation the protein is predicted to be. Insome embodiments of a protein, the protein has an aggregation score of 2or less. In some embodiments of a protein, the protein has anaggregation score of 1.5 or less. In some embodiments of a protein, theprotein has an aggregation score of 1 or less. In some embodiments of aprotein, the protein has an aggregation score of 0.9 or less. In someembodiments of a protein, the protein has an aggregation score of 0.8 orless. In some embodiments of a protein, the protein has an aggregationscore of 0.7 or less. In some embodiments of a protein, the protein hasan aggregation score of 0.6 or less. In some embodiments of a protein,the protein has an aggregation score of 0.5 or less. In some embodimentsof a protein, the protein has an aggregation score of 0.4 or less. Insome embodiments of a protein, the protein has an aggregation score of0.3 or less. In some embodiments of a protein, the protein has anaggregation score of 0.2 or less. In some embodiments of a protein, theprotein has an aggregation score of 0.1 or less.

In some cases, soluble expression is desirable because it can increasethe amount and/or yield of the protein and facilitate one or more of theisolation and purification of the protein. In some embodiments, theproteins of this disclosure are solubly expressed in the host organism.Solvation score and aggregation score can be used to predict solubleexpression of recombinant proteins in a host organism. As shown inExample 8, this disclosure provides evidence suggesting that proteinswith solvation scores of ≦−20 and aggregation scores of ≦0.75 are morelikely to be recombinantly expressed in a particular E. coli expressionsystem. Moreover, the data also suggests that proteins with solvationscores of ≦−20 and aggregation scores of ≦0.5 are more likely to besolubly expressed in this system. Therefore, in some embodiments theprotein of this disclosure has a solvation score of −20 or less. In someembodiments the nutritive protein has an aggregation score of 0.75 orless. In some embodiments the nutritive protein has an aggregation scoreof 0.5 or less. In some embodiments the protein has a solvation score of−20 or less and an aggregation score of 0.75 or less. In someembodiments the protein has a solvation score of −20 or less and anaggregation score of 0.5 or less.

Taste and Mouth Characteristics

Certain free amino acids and mixtures of free amino acids are known tohave a bitter or otherwise unpleasant taste. In addition, hydrolysatesof common proteins (e.g., whey and soy) often have a bitter orunpleasant taste. In some embodiments, proteins disclosed and describedherein do not have a bitter or otherwise unpleasant taste. In someembodiments, proteins disclosed and described herein have a moreacceptable taste as compared to at least one of free amino acids,mixtures of free amino acids, and/or protein hydrolysates. In someembodiments, proteins disclosed and described herein have a taste thatis equal to or exceeds at least one of whey protein.

Proteins are known to have tastes covering the five established tastemodalities: sweet, sour, bitter, salty, and umami. Fat can be considereda sixth taste. The taste of a particular protein (or its lack thereof)can be attributed to several factors, including the primary structure,the presence of charged side chains, and the electronic andconformational features of the protein. In some embodiments, proteinsdisclosed and described herein are designed to have a desired taste(e.g., sweet, salty, umami) and/or not to have an undesired taste (e.g.,bitter, sour). In this context “design” includes, for example, selectingedible species proteins embodying features that achieve the desiredtaste property, as well as creating muteins of edible speciespolypeptides that have desired taste properties. For example, proteinscan be designed to interact with specific taste receptors, such as sweetreceptors (TIR2-TIR3 heterodimer) or umami receptors (TIR1-TIR3heterodimer, mGluR4, and/or mGluR1). Further, proteins can be designednot to interact, or to have diminished interaction, with other tastereceptors, such as bitter receptors (T2R receptors).

Proteins disclosed and described herein can also elicit differentphysical sensations in the mouth when ingested, sometimes referred to as“mouth feel.” The mouth feel of the proteins can be due to one or morefactors including primary structure, the presence of charged sidechains, and the electronic and conformational features of the protein.In some embodiments, proteins elicit a buttery or fat-like mouth feelwhen ingested.

Nutritive Compositions and Formulations

At least one protein disclosed herein can be combined with at least onesecond component to form a composition. In some embodiments the onlysource of amino acid in the composition is the at least one proteindisclosed herein. In such embodiments the amino acid composition of thecomposition will be the same as the amino acid composition of the atleast one protein disclosed herein. In some embodiments the compositioncomprises at least one protein disclosed herein and at least one secondprotein. In some embodiments the at least one second protein is a secondprotein disclosed herein, while in other embodiments the at least onesecond protein is not a protein disclosed herein. In some embodimentsthe composition comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20 or more proteins disclosed herein. In someembodiments the composition comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more proteins that are notproteins disclosed herein. In some embodiments the composition comprises1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 ormore proteins and the composition comprises 0, 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more proteins that arenot proteins disclosed herein.

Also provided are formulations containing the nutritive polypeptidesdescribed herein. In one aspect, provided is a formulation containing aunicellular organism secreted polypeptide nutritional domain. Forexample, the polypeptide nutritional domain contains an amino acidsequence having an N-terminal amino acid that does not correspond to theN-terminal amino acid of an amino acid sequence comprising a unicellularorganism secreted polypeptide that contains the polypeptide nutritionaldomain. In some embodiments the amino acid sequence comprising theunicellular organism secreted polypeptide is an edible speciespolypeptide sequence, and the N-terminal amino acid is a common ediblespecies amino acid. In addition or in the alternative, the polypeptidenutritional domain contains an amino acid sequence having a C-terminalamino acid that does not correspond to the C-terminal amino acid of anamino acid sequence comprising a unicellular organism secretedpolypeptide that contains the polypeptide nutritional domain. In someembodiments the amino acid sequence comprising the unicellular organismsecreted polypeptide is an edible species polypeptide sequence, and theC-terminal amino acid is a common edible species amino acid. Thus, insome embodiments the secreted polypeptide nutritional domain is at leastone amino acid shorter than a homologous edible species polypeptide. Thenutritional domain can be about 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%,75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%or less than 5% the length of a homologous edible species peptide. Inother embodiments, the polypeptide nutritional domain consists of fromabout 1% to about 99% of the unicellular organism secreted polypeptidethat contains the polypeptide nutritional domain. As described herein,the polypeptide nutritional domain is generally preferred to the largerpolypeptide containing the polypeptide nutritional domain. A polypeptidenutritional domain may contain, on a mass basis, more nutrition than thelarger including polypeptide. In some embodiments, a polypeptidenutritional domain may provide desirable features when compared to thelarger including polypeptide, such as increased solubility and bettershelf-life stability.

In some embodiments the composition as described in the precedingparagraph, further comprises at least one of at least one polypeptide,at least one peptide, and at least one free amino acid. In someembodiments the composition comprises at least one polypeptide and atleast one peptide. In some embodiments the composition comprises atleast one polypeptide and at least one free amino acid. In someembodiments the composition comprises at least one peptide and at leastone free amino acid. In some embodiments the at least one polypeptide,at least one peptide, and/or at least one free amino acid comprisesamino acids selected from 1) branched chain amino acids, 2) leucine, and3) essential amino acids. In some embodiments the at least onepolypeptide, at least one peptide, and/or at least one free amino acidconsists of amino acids selected from 1) branched chain amino acids, 2)leucine, and 3) essential amino acids. In some embodiments, thecomposition comprises at least one modified amino acid or a non-standardamino acid. Modified amino acids include amino acids that havemodifications to one or more of the carboxy terminus, amino terminus,and/or side chain. Non-standard amino acids can be selected from thosethat are formed by post-translational modification of proteins, forexample, carboxylated glutamate, hydroxyproline, or hypusine. Othernon-standard amino acids are not found in proteins. Examples includelanthionine, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyricacid, omithine and citrulline. In some embodiments, the compositioncomprises one or more D-amino acids. In some embodiments, thecomposition comprises one or more L-amino acids. In some embodiments,the composition comprises a mixture of one or more D-amino acids and oneor more L-amino acids.

By adding at least one of a polypeptide, a peptide, and a free aminoacid to a composition the proportion of at least one of branched chainamino acids, leucine, and essential amino acids, to total amino acid,present in the composition can be increased.

In some embodiments the composition comprises at least one carbohydrate.A “carbohydrate” refers to a sugar or polymer of sugars. The terms“saccharide,” “polysaccharide,” “carbohydrate,” and “oligosaccharide”can be used interchangeably. Most carbohydrates are aldehydes or ketoneswith many hydroxyl groups, usually one on each carbon atom of themolecule. Carbohydrates generally have the molecular formula CnH2nOn. Acarbohydrate can be a monosaccharide, a disaccharide, trisaccharide,oligosaccharide, or polysaccharide. The most basic carbohydrate is amonosaccharide, such as glucose, sucrose, galactose, mannose, ribose,arabinose, xylose, and fructose. Disaccharides are two joinedmonosaccharides. Exemplary disaccharides include sucrose, maltose,cellobiose, and lactose. Typically, an oligosaccharide includes betweenthree and six monosaccharide units (e.g., raffinose, stachyose), andpolysaccharides include six or more monosaccharide units. Exemplarypolysaccharides include starch, glycogen, and cellulose. Carbohydratesmay contain modified saccharide units such as 2′-deoxyribose wherein ahydroxyl group is removed, 2′-fluororibose wherein a hydroxyl group isreplace with a fluorine, or N-acetylglucosamine, a nitrogen-containingform of glucose (e.g., 2′-fluororibose, deoxyribose, and hexose).Carbohydrates may exist in many different forms, for example,conformers, cyclic forms, acyclic forms, stereoisomers, tautomers,anomers, and isomers.

In some embodiments the composition comprises at least one lipid. Asused herein a “lipid” includes fats, oils, triglycerides, cholesterol,phospholipids, fatty acids in any form including free fatty acids. Fats,oils and fatty acids can be saturated, unsaturated (cis or trans) orpartially unsaturated (cis or trans). In some embodiments the lipidcomprises at least one fatty acid selected from lauric acid (12:0),myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16:1),margaric acid (17:0), heptadecenoic acid (17:1), stearic acid (18:0),oleic acid (18:1), linoleic acid (18:2), linolenic acid (18:3),octadecatetraenoic acid (18:4), arachidic acid (20:0), eicosenoic acid(20:1), eicosadienoic acid (20:2), eicosatetraenoic acid (20:4),eicosapentaenoic acid (20:5) (EPA), docosanoic acid (22:0), docosenoicacid (22:1), docosapentaenoic acid (22:5), docosahexaenoic acid (22:6)(DHA), and tetracosanoic acid (24:0). In some embodiments thecomposition comprises at least one modified lipid, for example a lipidthat has been modified by cooking.

In some embodiments the composition comprises at least one supplementalmineral or mineral source. Examples of minerals include, withoutlimitation: chloride, sodium, calcium, iron, chromium, copper, iodine,zinc, magnesium, manganese, molybdenum, phosphorus, potassium, andselenium. Suitable forms of any of the foregoing minerals includesoluble mineral salts, slightly soluble mineral salts, insoluble mineralsalts, chelated minerals, mineral complexes, non-reactive minerals suchas carbonyl minerals, and reduced minerals, and combinations thereof

In some embodiments the composition comprises at least one supplementalvitamin. The at least one vitamin can be fat-soluble or water solublevitamins. Suitable vitamins include but are not limited to vitamin C,vitamin A, vitamin E, vitamin B12, vitamin K, riboflavin, niacin,vitamin D, vitamin B6, folic acid, pyridoxine, thiamine, pantothenicacid, and biotin. Suitable forms of any of the foregoing are salts ofthe vitamin, derivatives of the vitamin, compounds having the same orsimilar activity of the vitamin, and metabolites of the vitamin.

In some embodiments the composition comprises at least one organism.Suitable examples are well known in the art and include probiotics(e.g., species of Lactobacillus or Bifidobacterium), spirulina,chlorella, and porphyra.

In some embodiments the composition comprises at least one dietarysupplement. Suitable examples are well known in the art and includeherbs, botanicals, and certain hormones. Non limiting examples includeginko, gensing, and melatonin.

In some embodiments the composition comprises an excipient. Non-limitingexamples of suitable excipients include a tastant, a flavorant, abuffering agent, a preservative, a stabilizer, a binder, a compactionagent, a lubricant, a dispersion enhancer, a disintegration agent, aflavoring agent, a sweetener, a coloring agent.

In some embodiments the excipient is a buffering agent. Non-limitingexamples of suitable buffering agents include sodium citrate, magnesiumcarbonate, magnesium bicarbonate, calcium carbonate, and calciumbicarbonate.

In some embodiments the excipient comprises a preservative. Non-limitingexamples of suitable preservatives include antioxidants, such asalpha-tocopherol and ascorbate, and antimicrobials, such as parabens,chlorobutanol, and phenol.

In some embodiments the composition comprises a binder as an excipient.Non-limiting examples of suitable binders include starches,pregelatinized starches, gelatin, polyvinylpyrolidone, cellulose,methylcellulose, sodium carboxymethylcellulose, ethylcellulose,polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fattyacid alcohol, polyethylene glycol, polyols, saccharides,oligosaccharides, and combinations thereof.

In some embodiments the composition comprises a lubricant as anexcipient. Non-limiting examples of suitable lubricants includemagnesium stearate, calcium stearate, zinc stearate, hydrogenatedvegetable oils, sterotex, polyoxyethylene monostearate, talc,polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, magnesiumlauryl sulfate, and light mineral oil.

In some embodiments the composition comprises a dispersion enhancer asan excipient. Non-limiting examples of suitable dispersants includestarch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin,bentonite, purified wood cellulose, sodium starch glycolate,isoamorphous silicate, and microcrystalline cellulose as high HLBemulsifier surfactants.

In some embodiments the composition comprises a disintegrant as anexcipient. In some embodiments the disintegrant is a non-effervescentdisintegrant. Non-limiting examples of suitable non-effervescentdisintegrants include starches such as corn starch, potato starch,pregelatinized and modified starches thereof, sweeteners, clays, such asbentonite, micro-crystalline cellulose, alginates, sodium starchglycolate, gums such as agar, guar, locust bean, karaya, pecitin, andtragacanth. In some embodiments the disintegrant is an effervescentdisintegrant. Non-limiting examples of suitable effervescentdisintegrants include sodium bicarbonate in combination with citricacid, and sodium bicarbonate in combination with tartaric acid.

In some embodiments the excipient comprises a flavoring agent. Flavoringagents incorporated into the outer layer can be chosen from syntheticflavor oils and flavoring aromatics; natural oils; extracts from plants,leaves, flowers, and fruits; and combinations thereof. In someembodiments the flavoring agent is selected from cinnamon oils; oil ofwintergreen; peppermint oils: clover oil; hay oil; anise oil;eucalyptus; vanilla; citrus oil such as lemon oil, orange oil grape andgrapefruit oil; and fruit essences including apple, peach, pear,strawberry, raspberry, cherry, plum, pineapple, and apricot.

In some embodiments the excipient comprises a sweetener. Non-limitingexamples of suitable sweeteners include glucose (corn syrup), dextrose,invert sugar, fructose, and mixtures thereof (when not used as acarrier); saccharin and its various salts such as the sodium salt;dipeptide sweeteners such as aspartame; dihydrochalcone compounds,glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives ofsucrose such as sucralose; and sugar alcohols such as sorbitol,mannitol, sylitol, and the like. Also contemplated are hydrogenatedstarch hydrolysates and the synthetic sweetener3,6-dihydro-6-methyl-1,2,3-oxathiazin-4-one-2,2-dioxide, particularlythe potassium salt (acesulfame-K), and sodium and calcium salts thereof.

In some embodiments the composition comprises a coloring agent.Non-limiting examples of suitable color agents include food, drug andcosmetic colors (FD&C), drug and cosmetic colors (D&C), and externaldrug and cosmetic colors (Ext. D&C). The coloring agents can be used asdyes or their corresponding lakes.

The weight fraction of the excipient or combination of excipients in theformulation is usually about 50% or less, about 45% or less, about 40%or less, about 35% or less, about 30% or less, about 25% or less, about20% or less, about 15% or less, about 10% or less, about 5% or less,about 2% or less, or about 1% or less of the total weight of the aminoacids in the composition.

The proteins and compositions disclosed herein can be formulated into avariety of forms and administered by a number of different means. Thecompositions can be administered orally, rectally, or parenterally, informulations containing conventionally acceptable carriers, adjuvants,and vehicles as desired. The term “parenteral” as used herein includessubcutaneous, intravenous, intramuscular, or intrasternal injection andinfusion techniques. In an exemplary embodiment, the protein orcomposition is administered orally.

Solid dosage forms for oral administration include capsules, tablets,caplets, pills, troches, lozenges, powders, and granules. A capsuletypically comprises a core material comprising a protein or compositionand a shell wall that encapsulates the core material. In someembodiments the core material comprises at least one of a solid, aliquid, and an emulsion. In some embodiments the shell wall materialcomprises at least one of a soft gelatin, a hard gelatin, and a polymer.Suitable polymers include, but are not limited to: cellulosic polymerssuch as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), methyl cellulose, ethyl cellulose, celluloseacetate, cellulose acetate phthalate, cellulose acetate trimellitate,hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulosesuccinate and carboxymethylcellulose sodium; acrylic acid polymers andcopolymers, such as those formed from acrylic acid, methacrylic acid,methyl acrylate, ammonio methylacrylate, ethyl acrylate, methylmethacrylate and/or ethyl methacrylate (e.g., those copolymers soldunder the trade name “Eudragit”); vinyl polymers and copolymers such aspolyvinyl pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate,vinylacetate crotonic acid copolymer, and ethylene-vinyl acetatecopolymers; and shellac (purified lac). In some embodiments at least onepolymer functions as taste-masking agents.

Tablets, pills, and the like can be compressed, multiply compressed,multiply layered, and/or coated. The coating can be single or multiple.In one embodiment, the coating material comprises at least one of asaccharide, a polysaccharide, and glycoproteins extracted from at leastone of a plant, a fungus, and a microbe. Non-limiting examples includecorn starch, wheat starch, potato starch, tapioca starch, cellulose,hemicellulose, dextrans, maltodextrin, cyclodextrins, inulins, pectin,mannans, gum arabic, locust bean gum, mesquite gum, guar gum, gumkaraya, gum ghatti, tragacanth gum, funori, carrageenans, agar,alginates, chitosans, or gellan gum. In some embodiments the coatingmaterial comprises a protein. In some embodiments the coating materialcomprises at least one of a fat and oil. In some embodiments the atleast one of a fat and an oil is high temperature melting. In someembodiments the at least one of a fat and an oil is hydrogenated orpartially hydrogenated. In some embodiments the at least one of a fatand an oil is derived from a plant. In some embodiments the at least oneof a fat and an oil comprises at least one of glycerides, free fattyacids, and fatty acid esters. In some embodiments the coating materialcomprises at least one edible wax. The edible wax can be derived fromanimals, insects, or plants. Non-limiting examples include beeswax,lanolin, bayberry wax, carnauba wax, and rice bran wax. Tablets andpills can additionally be prepared with enteric coatings.

Alternatively, powders or granules embodying the proteins andcompositions disclosed herein can be incorporated into a food product.In some embodiments the food product is be a drink for oraladministration. Non-limiting examples of a suitable drink include fruitjuice, a fruit drink, an artificially flavored drink, an artificiallysweetened drink, a carbonated beverage, a sports drink, a liquid diaryproduct, a shake, an alcoholic beverage, a caffeinated beverage, infantformula and so forth. Other suitable means for oral administrationinclude aqueous and nonaqueous solutions, creams, pastes, emulsions,suspensions and slurries, each of which may optionally also containingat least one of suitable solvents, preservatives, emulsifying agents,suspending agents, diluents, sweeteners, coloring agents, a tastant, aflavorant, and flavoring agents.

In some embodiments the food product is a solid foodstuff. Suitableexamples of a solid foodstuff include without limitation a food bar, asnack bar, a cookie, a brownie, a muffin, a cracker, a biscuit, a creamor paste, an ice cream bar, a frozen yogurt bar, and the like.

In some embodiments, the proteins and compositions disclosed herein areincorporated into a therapeutic food. In some embodiments, thetherapeutic food is a ready-to-use food that optionally contains some orall essential macronutrients and micronutrients. In some embodiments,the proteins and compositions disclosed herein are incorporated into asupplementary food that is designed to be blended into an existing meal.In some embodiments, the supplemental food contains some or allessential macronutrients and micronutrients. In some embodiments, theproteins and compositions disclosed herein are blended with or added toan existing food to fortify the food's protein nutrition. Examplesinclude food staples (grain, salt, sugar, cooking oil, margarine),beverages (coffee, tea, soda, beer, liquor, sports drinks), snacks,sweets and other foods.

The compositions disclosed herein can be utilized in methods to increaseat least one of muscle mass, strength and physical function,thermogenesis, metabolic expenditure, satiety, mitochondrial biogenesis,weight or fat loss, and lean body composition for example.

A formulation can contain a nutritive polypeptide up to about 25 g per100 kilocalories (25 g/100 kcal) in the formulation, meaning that all oressentially all of the energy present in the formulation is in the formof the nutritive polypeptide. More typically, about 99%, 98%, 97%, 96%,95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%,25%, 20%, 15%, 10%, 5% or less than 5% of the energy present in theformulation is in the form of the nutritive polypeptide. In otherformulations, the nutritive polypeptide is present in an amountsufficient to provide a nutritional benefit equivalent to or greaterthan at least about 0.1% of a reference daily intake value ofpolypeptide. Suitable reference daily intake values for protein are wellknown in the art. See, e.g., Dietary Reference Intakes for Energy,Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein and AminoAcids, Institute of Medicine of the National Academies, 2005, NationalAcademies Press, Washington DC. A reference daily intake value forprotein is a range wherein 10-35% of daily calories are provided byprotein and isolated amino acids. Another reference daily intake valuebased on age is provided as grams of protein per day: children ages 1-3:13 g children ages 4-8: 19 g, children ages 9-13: 34 g, girls ages14-18: 46, boys ages 14-18: 52, women ages 19-70+: 46, and men ages19-70+: 56. In other formulations, the nutritive polypeptide is presentin an amount sufficient to provide a nutritional benefit to a humansubject suffering from protein malnutrition or a disease, disorder orcondition characterized by protein malnutrition. Protein malnutrition iscommonly a prenatal or childhood condition. Protein malnutrition withadequate energy intake is termed kwashiorkor or hypoalbuminemicmalnutrition, while inadequate energy intake in all forms, includinginadequate protein intake, is termed marasmus. Adequately nourishedindividuals can develop sarcopenia from consumption of too littleprotein or consumption of proteins deficient in nutritive amino acids.Prenatal protein malnutrition can be prevented, treated or reduced byadministration of the nutritive polypeptides described herein topregnant mothers, and neonatal protein malnutrition can be prevented,treated or reduced by administration of the nutritive polypeptidesdescribed herein to the lactation mother. In adults, proteinmalnutrition is commonly a secondary occurrence to cancer, chronic renaldisease, and in the elderly. Additionally, protein malnutrition can bechronic or acute. Examples of acute protein malnutrition occur during anacute illness or disease such as sepsis, or during recovery from atraumatic injury, such as surgery, thermal injury such as a burn, orsimilar events resulting in substantial tissue remodeling. Other acuteillnesses treatable by the methods and compositions described hereininclude sarcopenia, cachexia, diabetes, insulin resistance, and obesity.

A formulation can contain a nutritive polypeptide in an amountsufficient to provide a feeling of satiety when consumed by a humansubject, meaning the subject feels a reduced sense or absence of hunger,or desire to eat. Such a formulation generally has a higher satietyindex than carbohydrate-rich foods on an equivalent calorie basis.

A formulation can contain a nutritive polypeptide in an amount based onthe concentration of the nutritive polypeptide (e.g., on aweight-to-weight basis), such that the nutritive polypeptide accountsfor up to 100% of the weight of the formulation, meaning that all oressentially all of the matter present in the formulation is in the formof the nutritive polypeptide. More typically, about 99%, 98%, 97%, 96%,95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%,25%, 20%, 15%, 10%, 5% or less than 5% of the weight present in theformulation is in the form of the nutritive polypeptide. In someembodiments, the formulation contains 10 mg, 100 mg, 500 mg, 750 mg, 1g, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9, 10 g, 15 g, 20 g, 25 g, 30 g,35 g, 40 g, 45 g, 50 g, 60 g, 70 g, 80 g, 90 g, 100 g or over 100 g ofnutritive polypeptide.

Preferably, the formulations provided herein are substantially free ofnon-comestible products. Non-comestible products are often found inpreparations of recombinant proteins of the prior art, produced fromyeast, bacteria, algae, insect, mammalian or other expression systems.Exemplary non-comestible products include surfactant, a polyvinylalcohol, a propylene glycol, a polyvinyl acetate, apolyvinylpyrrolidone, a non-comestible polyacid or polyol a fattyalcohol, an alkylbenzyl sulfonate, an alkyl glucoside, or a methylparaben.

In aspects, the provided formulations contain other materials, such as atastant, a nutritional carbohydrate and/or a nutritional lipid. Inaddition, formulations may include bulking agents, texturizers, andfillers.

In preferred embodiments, the nutritive polypeptides provided herein areisolated and/or substantially purified. The nutritive polypeptides andthe compositions and formulations provided herein, are substantiallyfree of non-protein components. Such non-protein components aregenerally present in protein preparations such as whey, casein, egg andsoy preparations, which contain substantial amounts of carbohydrates andlipids that complex with the polypeptides and result in delayed andincomplete protein digestion in the gastrointestinal tract. Suchnon-protein components can also include DNA. Thus, the nutritivepolypeptides, compositions and formulations are characterized byimproved digestibility and decreased allergenicity as compared tofood-derived polypeptides and polypeptide mixtures. Furthermore, theseformulations and compositions are characterized by more reproducibledigestibility from a time and/or a digestion product at a given unittime basis. In certain embodiments, a nutritive polypeptide is at least10% reduced in lipids and/or carbohydrates, and optionally one or moreother materials that decreases digestibility and/or increasesallergenicity, relative to a reference polypeptide or referencepolypeptide mixture, e.g., is reduced by 20%, 30%, 40%, 50%, 60%, 70%,80%, 90%, 95%, 99% or greater than 99%. In certain embodiments, thenutritive formulations contain a nutritional carbohydrate and/ornutritional lipid, which may be selected for digestibility and/orreduced allergenicity.

Methods of Use

In some embodiments the proteins and compositions disclosed herein areadministered to a patient or a user (sometimes collectively referred toas a “subject”). As used herein “administer” and “administration”encompasses embodiments in which one person directs another to consume aprotein or composition in a certain manner and/or for a certain purpose,and also situations in which a user uses a protein or composition in acertain manner and/or for a certain purpose independently of or invariance to any instructions received from a second person. Non-limitingexamples of embodiments in which one person directs another to consume aprotein or composition in a certain manner and/or for a certain purposeinclude when a physician prescribes a course of conduct and/or treatmentto a patient, when a trainer advises a user (such as an athlete) tofollow a particular course of conduct and/or treatment, and when amanufacturer, distributor, or marketer recommends conditions of use toan end user, for example through advertisements or labeling on packagingor on other materials provided in association with the sale or marketingof a product.

In some embodiments the proteins or compositions are provided in adosage form. In some embodiments the dosage form is designed foradministration of at least one protein disclosed herein, wherein thetotal amount of protein administered is selected from 0.1 g to 1 g, 1 gto 5 g. from 2 g to 10 g, from 5 g to 15 g, from 10 g to 20 g. from 15 gto 25 g, from 20 g to 40 g, from 25-50 g, and from 30-60 g. In someembodiments the dosage form is designed for administration of at leastone protein disclosed herein, wherein the total amount of proteinadministered is selected from about 0.1 g, 0.1 g-1 g, 1 g, 2 g, 3 g, 4g, 5 g, 6 g, 7 g, 8 g, 9 g, 10 g, 15 g, 20 g, 25 g, 30 g, 35 g, 40 g, 45g, 50 g, 55 g, 60 g, 65 g, 70 g, 75 g, 80 g, 85 g, 90 g, 95 g. and 100g.

In some embodiments the dosage form is designed for administration of atleast one protein disclosed herein, wherein the total amount ofessential amino acids administered is selected from 0.1 g to 1 g, from 1g to 5 g, from 2 g to 10 g, from 5 g to 15 g. from 10 g to 20 g, andfrom 1-30 g. In some embodiments the dosage form is designed foradministration of at least one protein disclosed herein, wherein thetotal amount of protein administered is selected from about 0.1 g, 0.1-1g, 1 g, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9 g, 10 g, 15 g, 20 g, 25 g,30 g, 35 g, 40 g, 45 g, 50 g, 55 g, 60 g, 65 g, 70 g, 75 g., 80 g, 85 g,90 g, 95 g. and 100 g.

In some embodiments the protein or composition is consumed at a rate offrom 0.1 g to 1 g a day, 1 g to 5 g a day, from 2 g to 10 g a day, from5 g to 15 g a day, from 10 g to 20 g a day, from 15 g to 30 g a day,from 20 g to 40 g a day, from 25 g to 50 g a day, from 40 g to 80 g aday, from 50 g to 100 g a day, or more.

In some embodiments, of the total protein intake by the subject, atleast 5%, at least 10%, at least 15%, at least 20%, at least 25%, atleast 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90%, at least 95%, or about 100% ofthe total protein intake by the subject over a dietary period is made upof at least one protein according to this disclosure. In someembodiments, of the total protein intake by the subject, from 5% to 100%of the total protein intake by the subject, from 5% to 90% of the totalprotein intake by the subject, from 5% to 80% of the total proteinintake by the subject, from 5% to 70% of the total protein intake by thesubject, from 5% to 60% of the total protein intake by the subject, from5% to 50% of the total protein intake by the subject, from 5% to 40% ofthe total protein intake by the subject, from 5% to 30% of the totalprotein intake by the subject, from 5% to 20% of the total proteinintake by the subject, from 5% to 10% of the total protein intake by thesubject, from 10% to 100% of the total protein intake by the subject,from 10% to 100% of the total protein intake by the subject, from 20% to100% of the total protein intake by the subject, from 30% to 100% of thetotal protein intake by the subject, from 40% to 100% of the totalprotein intake by the subject, from 50% to 100% of the total proteinintake by the subject, from 60% to 100% of the total protein intake bythe subject, from 70% to 100% of the total protein intake by thesubject, from 80% to 100% of the total protein intake by the subject, orfrom 90% to 100% of the total protein intake by the subject, over adietary period, is made up of at least one protein according to thisdisclosure. In some embodiments the at least one protein of thisdisclosure accounts for at least 5%, at least 10%, at least 15%, atleast 20%, at least 25%, at least 30%, at least 35%, at least 40%, atleast 45%, or at least 50% of the subject's calorie intake over adietary period.

In some embodiments the at least one protein according to thisdisclosure comprises at least 2 proteins of this disclosure, at least 3proteins of this disclosure, at least 4 proteins of this disclosure, atleast 5 proteins of this disclosure, at least 6 proteins of thisdisclosure, at least 7 proteins of this disclosure, at least 8 proteinsof this disclosure, at least 9 proteins of this disclosure, at least 10proteins of this disclosure, or more.

In some embodiments the dietary period is I meal 2 meals, 3 meals, atleast 1 day, at least 2 days, at least 3 days, at least 4 days, at least5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3months, at least 4 months, at least 5 months, at least 6 months, or atleast 1 year. In some embodiments the dietary period is from 1 day to 1week, from 1 week to 4 weeks, from 1 month, to 3 months, from 3 monthsto 6 months, or from 6 months to 1 year.

Clinical studies provide evidence that protein prevents muscle loss dueto aging or disuse, such as from immobility or prolonged bed rest. Inparticular, studies have shown that protein supplementation increasesmuscle fractional synthetic rate (FSR) during prolonged bed rest,maintains leg mass and strength during prolonged bed rest, increaseslean body mass, improves functional measures of gait and balance, andmay serve as a viable intervention for individuals at risk of sarcopeniadue to immobility or prolonged bed rest. See. e.g., Paddon-Jones D, etal. J Clin Endocrinol Metab 2004, 89:4351-4358; Ferrando, A et al.Clinical Nutrition 2009 1-6; Katsanos C et al. Am J Physiol EndocrinolMetab. 2006, 291: 381-387.

Studies on increasing muscle protein anabolism in athletes have shownthat protein provided following exercise promotes muscle hypertrophy toa greater extent than that achieved by exercise alone. It has also beenshown that protein provided following exercise supports proteinsynthesis without any increase in protein breakdown, resulting in a netpositive protein balance and muscle mass accretion. While muscle proteinsynthesis appears to respond in a dose-response fashion to essentialamino acid supplementation, not all proteins are equal in buildingmuscle. For example, the amino acid leucine is an important factor instimulating muscle protein synthesis. See, e.g., & Borscheim E et al. AmJ Physiol Endocrinol Metab 2002, 283: E648-E657; Borsheim E et al. ClinNutr. 2008, 27: 189-95; Esmarck B et al J Physiol 2001, 535: 301-311;Moore D et al. Am J Clin Nutr 2009, 89: 161-8).

In another aspect this disclosure provides methods of maintaining orincreasing at least one of muscle mass, muscle strength, and functionalperformance in a subject. In some embodiments the methods compriseproviding to the subject a sufficient amount of a protein of thisdisclosure, a composition of this disclosure, or a composition made by amethod of this disclosure. In some embodiments the subject is at leastone of elderly, critically-medically ill, and suffering fromprotein-energy malnutrition. In some embodiments the sufficient amountof a protein of this disclosure, a composition of this disclosure, or acomposition made by a method of this disclosure is consumed by thesubject in coordination with performance of exercise. In someembodiments the protein of this disclosure, composition of thisdisclosure, or composition made by a method of this disclosure isconsumed by the subject by an oral, enteral, or parenteral route. Insome embodiments the protein of this disclosure, composition of thisdisclosure, or composition made by a method of this disclosure isconsumed by the subject by an oral route. In some embodiments theprotein of this disclosure, composition of this disclosure, orcomposition made by a method of this disclosure is consumed by thesubject by an enteral route.

In another aspect this disclosure provides methods of maintaining orachieving a desirable body mass index in a subject. In some embodimentsthe methods comprise providing to the subject a sufficient amount of aprotein of this disclosure, a composition of this disclosure, or acomposition made by a method of this disclosure. In some embodiments thesubject is at least one of elderly, critically-medically ill, andsuffering from protein-energy malnutrition. In some embodiments thesufficient amount of a protein of this disclosure, a composition of thisdisclosure, or a composition made by a method of this disclosure isconsumed by the subject in coordination with performance of exercise. Insome embodiments the protein of this disclosure, composition of thisdisclosure, or composition made by a method of this disclosure isconsumed by the subject by an oral, enteral, or parenteral route.

In another aspect this disclosure provides methods of providing proteinto a subject with protein-energy malnutrition. In some embodiments themethods comprise providing to the subject a sufficient amount of aprotein of this disclosure, a composition of this disclosure, or acomposition made by a method of this disclosure. In some embodiments theprotein of this disclosure, composition of this disclosure, orcomposition made by a method of this disclosure is consumed by thesubject by an oral, enteral, or parenteral route.

The need for essential amino acid supplementation has been suggested incancer patients and other patients suffering from muscle wasting andcachexia. Dietary studies in mice have shown survival and functionalbenefits to cachectic cancer-bearing mice through dietary interventionwith essential amino acids. Beyond cancer, essential amino acidsupplementation has also shown benefits, such as improved musclefunction and muscle gain, in patients suffering from other diseases thathave difficulty exercising and therefore suffer from musculardeterioration, such as chronic obstructive pulmonary disease, chronicheart failure, HIV, and other disease states.

Studies have shown that specific amino acids have advantages in managingcachexia. A relatively high content of BCAAs and Leu in diets arethought to have a positive effect in cachexia by promoting total proteinsynthesis by signaling an increase in translation, enhancing insulinrelease, and inhibiting protein degradation. Thus, consuming increaseddietary BCAAs in general and/or Leu in particular will contributepositively to reduce or reverse the effects of cachexia. Becausenitrogen balance is important in countering the underlying cause ofcachexia it is thought that consuming increased dietary glutamine and/orarginine will contribute positively to reduce or reverse the effects ofcachexia. See, e.g., Op den Kamp C, Langen R, Haegens A, Schols A.“Muscle atrophy in cachexia: can dietary protein tip the balance?”Current Opinion in Clinical Nutrition and Metabolic Care 2009,12:611-616; Poon RT-P, Yu W-C, Fan S-T, et al. “Long-term oral branchedchain amino acids in patients undergoing chemoembolization forhepatocellular carcinoma: a randomized trial.” Aliment Pharmacol Ther2004; 19:779 788; Tayek J A, Bistrian B R, Hehir D J, Martin R,Mokldawer L L, Blackburn G L. “Improved protein kinetics and albuminsynthesis by branched chain amino acid-enriched total parenteralnutrition in cancer cachexia.” Cancer. 1986; 58:147-57; Xi P, Jiang Z,Zheng C, Lin Y, Wu G “Regulation of protein metabolism by glutamine:implications for nutrition and health.” Front Biosci. 2011 Jan. 1;16:578-97.

Accordingly, also provided herein are methods of treating cachexia in asubject. In some embodiments a sufficient amount of a protein of thisdisclosure, a composition of this disclosure, or a composition made by amethod of this disclosure for a subject with cachexia is an amount suchthat the amount of protein of this disclosure ingested by the personmeets or exceeds the metabolic needs (which are often elevated). Aprotein intake of 1.5 g/kg of body weight per day or 15-20% of totalcaloric intake appears to be an appropriate target for persons withcachexia. In some embodiments all of the protein consumed by the subjectis a protein according to this disclosure. In some embodiments proteinaccording to this disclosure is combined with other sources of proteinand/or free amino acids to provide the total protein intake of thesubject. In some embodiments the subject is at least one of elderly,critically-medically ill, and suffering from protein-energymalnutrition. In some embodiments the subject suffers from a diseasethat makes exercise difficult and therefore causes musculardeterioration, such as chronic obstructive pulmonary disease, chronicheart failure, HIV, cancer, and other disease states. In someembodiments, the protein according to disclosure, the compositionaccording to disclosure, or the composition made by a method accordingto disclosure is consumed by the subject in coordination withperformance of exercise. In some embodiments, the protein according tothis disclosure, the composition according to disclosure, or thecomposition made by a method according to disclosure is consumed by thesubject by an oral, enteral, or parenteral route.

Sarcopenia is the degenerative loss of skeletal muscle mass (typically0.5-1% loss per year after the age of 25), quality, and strengthassociated with aging. Sarcopenia is a component of the frailtysyndrome. The European Working Group on Sarcopenia in Older People(EWGSOP) has developed a practical clinical definition and consensusdiagnostic criteria for age-related sarcopenia. For the diagnosis ofsarcopenia, the working group has proposed using the presence of bothlow muscle mass and low muscle function (strength or performance).Sarcopenia is characterized first by a muscle atrophy (a decrease in thesize of the muscle), along with a reduction in muscle tissue “quality,”caused by such factors as replacement of muscle fibres with fat, anincrease in fibrosis, changes in muscle metabolism, oxidative stress,and degeneration of the neuromuscular junction. Combined, these changeslead to progressive loss of muscle function and eventually to frailty.Frailty is a common geriatric syndrome that embodies an elevated risk ofcatastrophic declines in health and function among older adults.Contributors to frailty can include sarcopenia, osteoporosis, and muscleweakness. Muscle weakness, also known as muscle fatigue, (or “lack ofstrength”) refers to the inability to exert force with one's skeletalmuscles. Weakness often follows muscle atrophy and a decrease inactivity, such as after a long bout of bedrest as a result of anillness. There is also a gradual onset of muscle weakness as a result ofsarcopenia.

The proteins of this disclosure are useful for treating sarcopenia orfrailty once it develops in a subject or for preventing the onset ofsarcopenia or frailty in a subject who is a member of an at risk groups.In some embodiments all of the protein consumed by the subject is aprotein according to this disclosure. In some embodiments proteinaccording to this disclosure is combined with other sources of proteinand/or free amino acids to provide the total protein intake of thesubject. In some embodiments the subject is at least one of elderly,critically-medically ill, and suffering from protein-energymalnutrition. In some embodiments, the protein according to disclosure,the composition according to disclosure, or the composition made by amethod according to disclosure is consumed by the subject incoordination with performance of exercise. In some embodiments, theprotein according to this disclosure, the composition according todisclosure, or the composition made by a method according to disclosureis consumed by the subject by an oral, enteral, or parenteral route.

Obesity is a multifactoral disorder associated with a host ofcomorbidities including hypertension, type 2 diabetes, dyslipidemia,coronary heart disease, stroke, cancer (eg, endometrial, breast, andcolon), osteoarthritis, sleep apnea, and respiratory problems. Theincidence of obesity, defined as a body mass index >30 kg/m2, hasincreased dramatically in the United States, from 15% (1976-1980) to 33%(2003-2004), and it continues to grow. Although the mechanismscontributing to obesity are complex and involve the interplay ofbehavioral components with hormonal, genetic, and metabolic processes,obesity is largely viewed as a lifestyle-dependent condition with 2primary causes: excessive energy intake and insufficient physicalactivity. With respect to energy intake, there is evidence that modestlyincreasing the proportion of protein in the diet, while controllingtotal energy intake, may improve body composition, facilitate fat loss,and improve body weight maintenance after weight loss. Positive outcomesassociated with increased dietary protein are thought to be dueprimarily to lower energy intake associated with increased satiety,reduced energy efficiency and/or increased thermogenesis, positiveeffects on body composition (specifically lean muscle mass), andenhanced glycemic control.

Dietary proteins are more effective in increasing post-prandial energyexpenditure than isocaloric intakes of carbohydrates or fat (see, e.g.,Dauncey M, Bingham S. “Dependence of 24 h energy expenditure in man oncomposition of the nutrient intake.” Br J Nutr 1983, 50: 1-13; Karst Het al. “Diet-induced thermogenesis in man: thermic effects of singleproteins, carbohydrates and fats depending on their energy amount.” AnnNutr Metab. 1984, 28: 245-52; Tappy L et al “Thermic effect of infusedamino acids in healthy humans and in subjects with insulin resistance.”Am J Clin Nutr 1993, 57 (6): 912-6). This property along with otherproperties (satiety induction: preservation of lean body mass) makeprotein an attractive component of diets directed at weight management.The increase in energy expenditure caused by such diets may in part bedue to the fact that the energy cost of digesting and metabolizingprotein is higher than for other calorie sources. Protein turnover,including protein synthesis, is an energy consuming process. Inaddition, high protein diets may also up-regulate uncoupling protein inliver and brown adipose, which is positively correlated with increasesin energy expenditure. It has been theorized that different proteins mayhave unique effects on energy expenditure.

Studies suggest that ingestion of protein, particularly proteins withhigh EAA and/or BCAA content, leads to distinct effects on thermogenesisand energy expenditure (see, e.g., Mikkelsen P. et al. “Effect offat-reduced diets on 24 h energy expenditure: comparisons between animalprotein, vegetable protein and carbohydrate.” Am J Clin Nutr 2000,72:1135-41; Acheson K. et al. “Protein choices targeting thermogenesisand metabolism.” Am J Clin Nutr 2011, 93:525-34; Alfenas R. et al.“Effects of protein quality on appetite and energy metabolism in normalweight subjects” Arg Bras Endocrinol Metabol 2010, 54 (1): 45-51;Lorenzen J. et al. “The effect of milk proteins on appetite regulationand diet-induced thermogenesis.” J Clin Nutr 2012 66 (5): 622-7).Additionally, L-tyrosine has been identified as an amino acid that playsa role in thermogenesis (see, e.g., Belza A. et al. “The beta-adrenergicantagonist propranolol partly abolishes thermogenic response tobioactive food ingredients.” Metabolism 2009, 58 (8):1137-44). Furtherstudies suggest that Leucine and Arginine supplementation appear toalter energy metabolism by directing substrate to lean body mass ratherthan adipose tissue (Dulloo A. “The search for compounds that stimulatethermogenesis in obesity management: from pharmaceuticals to functionalfood ingredients.” Obes Rev 2011 12: 866-83).

Collectively the literature suggests that different protein types leadsto distinct effects on thermogenesis. Because proteins or peptides richin EAAs, BCAA, and/or at least one of Tyr, Arg, and Leu are believed tohave a stimulatory effect on thermogenesis, and because stimulation ofthermogenesis is believed to lead to positive effects on weightmanagement, this disclosure also provides products and methods useful tostimulation thermogenesis and/or to bring about positive effects onweight management in general.

More particularly, this disclosure provides methods of increasingthermogenesis in a subject. In some embodiments the methods compriseproviding to the subject a sufficient amount of a protein of thisdisclosure, a composition of this disclosure, or a composition made by amethod of this disclosure. In some embodiments the subject is obese. Insome embodiments, the protein according to disclosure, the compositionaccording to disclosure, or the composition made by a method accordingto disclosure is consumed by the subject in coordination withperformance of exercise. In some embodiments, the protein according todisclosure, the composition according to disclosure, or the compositionmade by a method according to disclosure is consumed by the subject byan oral, enteral, or parenteral route.

At the basic level, the reason for the development of an overweightcondition is due to an imbalance between energy intake and energyexpenditure. Attempts to reduce food at any particular occasion(satiation) and across eating occasions (satiety) have been a majorfocus of recent research. Reduced caloric intake as a consequence offeeling satisfied during a meal and feeling full after a meal resultsfrom a complex interaction of internal and external signals. Variousnutritional studies have demonstrated that variation in food propertiessuch as energy density, content, texture and taste influence bothsatiation and satiety.

There are three macronutrients that deliver energy: fat, carbohydratesand proteins. A gram of protein or carbohydrate provides 4 calorieswhile a gram of fat 9 calories. Protein generally increases satiety to agreater extent than carbohydrates or fat and therefore may facilitate areduction in calorie intake. However, there is considerable evidencethat indicates the type of protein matters in inducing satiety (see,e.g., W. L. Hall, et al. “Casein and whey exert different effects onplasma amino acid profiles, gastrointestinal hormone secretion andappetite.” Br J Nutr. 2003 February, 89(2):239-48; R. Abou-Samra, et al.“Effect of different protein sources on satiation and short-term satietywhen consumed as a starter.” Nutr J. 2011 Dec. 23, 10:139; T. Akhavan,et al. “Effect of premeal consumption of whey protein and itshydrolysate on food intake and postmeal glycemia and insulin responsesin young adults.” Am J Clin Nutr. 2010 April 91(4):966-75. Epub 2010Feb. 17; MA Veldhorst “Dose-dependent satiating effect of whey relativeto casein or soy” Physiol Behav. 2009 Mar. 23, 96(4-5):675-82). Evidenceindicates that protein rich in Leucine is particularly effective atinducing satiety (see, e.g., Fromentin G et al “Peripheral and centralmechanisms involved in the control of food intake by dietary amino acidsand proteins.” Nutr Res Rev 2012 25: 29-39).

In some embodiments a protein of this disclosure is consumed by asubject concurrently with at least one pharmaceutical or biologic drugproduct. In some embodiments the beneficial effects of the protein andthe at least one pharmaceutical or biologic drug product have anadditive effect while in some embodiments the beneficial effects of theprotein and the at least one pharmaceutical or biologic drug producthave a synergistic effect. Examples of pharmaceutical or biologic drugproducts that can be administered with the proteins of this disclosureare well known in the art. For example, when a protein of thisdisclosure is used to maintain or increase at least one of muscle mass,muscle strength, and functional performance in a subject, the proteincan be consumed by a subject concurrently with a therapeutic dosageregime of at least one pharmaceutical or biologic drug product indicatedto maintain or increase at least one of muscle mass, muscle strength,and functional performance in a subject, such as an anabolic steroid.When a protein of this disclosure is used to maintain or achieve adesirable body mass index in a subject, the protein can be consumed by asubject concurrently with a therapeutic dosage regime of at least onepharmaceutical or biologic drug product indicated to maintain or achievea desirable body mass index in a subject, such as orlistat, lorcaserin,sibutramine, rimonabant, metformin, exenatide, or pramlintide. When aprotein of this disclosure is used to induce at least one of a satiationresponse and a satiety response in a subject, the protein can beconsumed by a subject concurrently with a therapeutic dosage regime ofat least one pharmaceutical or biologic drug product indicated to induceat least one of a satiation response and a satiety response in asubject, such as rimonabant, exenatide, or pramlintide. When a proteinof this disclosure is used to treat at least one of cachexia, sarcopeniaand frailty in a subject, the protein can be consumed by a subjectconcurrently with a therapeutic dosage regime of at least onepharmaceutical or biologic drug product indicated to treat at least oneof cachexia, sarcopenia and frailty, such as omega-3 fatty acids oranabolic steroids. Because of the role of dietary protein in inducingsatiation and satiety, the proteins and compositions disclosed hereincan be used to induce at least one of a satiation response and a satietyresponse in a subject. In some embodiments the methods compriseproviding to the subject a sufficient amount of a protein of thisdisclosure, a composition of this disclosure, or a composition made by amethod of this disclosure. In some embodiments the subject is obese. Insome embodiments, the protein according to disclosure, the compositionaccording to disclosure, or the composition made by a method accordingto disclosure is consumed by the subject in coordination withperformance of exercise. In some embodiments, the protein according todisclosure, the composition according to disclosure, or the compositionmade by a method according to disclosure is consumed by the subject byan oral, enteral, or parenteral route.

In some embodiments incorporating a least one protein or composition ofthis disclosure into the diet of a subject has at least one effectselected from inducing postprandial satiety (including by suppressinghunger), inducing thermogenesis, reducing glycemic response, positivelyaffecting energy expenditure positively affecting lean body mass,reducing the weight gain caused by overeating, and decreasing energyintake. In some embodiments incorporating a least one protein orcomposition of this disclosure into the diet of a subject has at leastone effect selected from increasing loss of body fat, reducing leantissue loss, improving lipid profile, and improving glucose toleranceand insulin sensitivity in the subject.

Examples of the techniques and protocols described herein can be foundin Remington's Pharmaceutical Sciences, 16th edition. Osol, A. (ed).1980.

EXAMPLES

Below are examples of specific embodiments for carrying out the presentinvention. The examples are offered for illustrative purposes only, andare not intended to limit the scope of the present invention in any way.Efforts have been made to ensure accuracy with respect to numbers used(e.g., amounts, temperatures, etc.), but some experimental error anddeviation should, of course, be allowed for.

The practice of the present invention will employ, unless otherwiseindicated, conventional methods of protein chemistry, biochemistry,recombinant DNA techniques and pharmacology, within the skill of theart. Such techniques are explained fully in the literature. See, e.g.,T. E. Creighton, Proteins: Structures and Molecular Properties (W.H.Freeman and Company, 1993); A. L. Lehninger, Biochemistry (WorthPublishers, Inc., current addition); Sambrook, et al., MolecularCloning: A Laboratory Manual (2nd Edition, 1989); Methods In Enzymology(S. Colowick and N. Kaplan eds., Academic Press, Inc.); Remington'sPharmaceutical Sciences, 18th Edition (Easton, Pa.: Mack PublishingCompany, 1990); Carey and Sundberg Advanced Organic Chemistry 3^(rd) Ed.(Plenum Press) Vols A and B(1992).

Example 1 Identification and Selection of Amino Acid Sequences ofNutritive Polypeptides of Edible Species Using Mass SpectrometricAnalyses

Provided is a process for identifying one or a plurality of nutritivepolypeptide amino acid sequences, such as from a polypeptide or nucleicacid library, or from a relevant database of protein sequences. Here,nutritive polypeptide amino acid sequences were identified by massspectroscopy analysis of proteins extracted and purified from ediblespecies.

Protein Isolation for Mass Spectroscopy.

Proteins were extracted from solid edible sources. Samples from thefollowing species were included in the analysis: Actinidia deliciosa,Agaricus bisporus var. bisporus, Arthrospira platensis, Bos taurus,Brassica oleracea, Cannabis, Chenopodium quinoa, Chlorella regularis,Chlorella variabilis, Cicer arietinum, Cucurbita maxima, Fusariumgraminearum, Gadus morhua, Gallus gallus, Glycine Max, Lactobacillusacidophilus, Laminariales, Linum usitatissimum, Meleagris gallopavo,Odocoileus virginianus, Oreochromis niloticus, Oryza sativa, Ovis aries,Palmaria palmnata, Persea americana, Prunus mume, Saccharomycescerevisiae, Salmo salar, Solanum lycopesicum, Solanum tuberosum, Susscrofa, Thunnus thymus, Vaccinium corymbosum, Vitis vinifera, and Zeamays. Each sample was first frozen at −80 C and then ground using amortar and pestle before weighing 50 mg of material into amicrocentrifuge tube. The 50 mg sample was then resuspended in 1 mL ofextraction buffer (8.3 M urea, 2 M thiourea, 2% w/v CHAPS, 1% w/v DTT)and agitated for 30 minutes. Addition of 500 μL of 100-μm zirconiumbeads (Ops Diagnostics) was followed by continued agitation for anadditional 30 minutes. Samples were run on a TissueLyser II (Qiagen) at30 Hz for 3 minutes and then centrifuged for 10 minutes at 21.130 g in abenchtop microcentrifuge (Eppendorf). Supernatants were transferred toclean microcentrifuge tubes, aliquoted into 50 μL aliquots, and storedat −80° C. The amount of soluble protein extracted was measured byCoomassie Plus (Bradford) Protein Assay (Thermo Scientific). 20 ug ofprotein was run on 10% 10-lane BisTris SDS-PAGE gel (Invitrogen) andthen excised for analysis by LC/MS/MS.

Proteins were also isolated from liquid cultures of the following edibleorganisms: Aspergillus niger, Bacillus subtilis, Bacillus licheniformis,and Bacillus amyloliquefaciens. Aspergillus and bacillus organisms werecultured as described herein. Clarified supernatants were isolated bycentrifuging (10,000×g) cultures for 10 minutes, followed by filteringthe supernatant using a 0.2 μM filter. The amount of soluble protein inthe clarified supernatant was measured by Coomassie Plus (Bradford)Protein Assay (Thermo Scientific). Protein samples (20 μg) were run on a10% Precast BisTris SDS-PAGE gel (Invitrogen) according to themanufacturer's protocol.

Mass Spectroscopy.

For LC/MS/MS analysis each gel was excised into five equally sizedpieces. Trypsin digestion was performed using a robot (ProGest, DigiLab)with the following protocol: washed with 25 mM ammonium bicarbonatefollowed by acetonitrile, reduced with 10 mM dithiothreitol at 60° C.followed by alkylation with 50 mM iodoacetamide at RT, digested withtrypsin (Promega) at 37° C. for 4 h, quenched with formic acid and thesupernatant was analyzed directly without further processing. The geldigests for each sample were pooled and analyzed by nano LC/MS/MS with aWaters NanoAcquity HPLC system interfaced to a ThermoFisher Q Exactive.Peptides were loaded on a trapping column and eluted over a 75 μmanalytical column at 350 nL/min; both columns were packed with JupiterProteco resin (Phenomenex). The mass spectrometer was operated indata-dependent mode, with MS and MS/MS performed in the Orbitrap at70,000 FWHM and 17,500 FWHM resolution, respectively. The fifteen mostabundant ions were selected for MS/MS. Resulting data were searchedagainst a Uniprot and/or NCBI protein database from the correspondingorganism using Mascot with the following parameters: Enzyme—Trypsin/P,Fixed modification—Carbamidomethyl (C) Variable modifications—Oxidation(M), Acetyl (Protein N-term). Pyro-Glu (N-term Q). Deamidation (NQ).Mass values—Monoisotopic, Peptide Mass Tolerance—10 ppm, Fragment MassTolerance—0.015 Da, Max Missed Cleavages—2. Mascot DAT files were parsedinto the Scaflold software for validation, filtering and to create anon-redundant list per sample. Data were filtered using a minimumprotein value of 90%, a minimum peptide value of 50% (Prophet scores)and requiring at least two unique peptides per protein. Relativeabundance of detected proteins was determined by spectral counts, whichis the number of spectra acquired for each protein. Spectral counting isa label-free quantification method commonly used by the protein massspec field (Liu, Hongbin et al. Analytical chemistry 76.14 (2004):4193-4201). To calculate the relative abundance of each protein in theprotein isolate the number of protein spectral counts is divided by thetotal protein spectral counts. SEQID 894-3415 were identified using thismethod.

Homolog Discovery.

For the nutritive polypeptide sequences identified, as described,similar sequences are identified from other species, SEQID-00093, whichwas identified by this method, was used to search for homologs using thecomputer program BLAST as described herein. Example nutritivepolypeptide homologs from the edible database identified in this way areshown in table E1A. Example nutritive polypeptide homologous from theexpressed sequence database identified in this way are shown in tableEIB.

TABLE E1A Edible Sequences identified as homologs to SEQID-00093. SEQIDEAA Percent ID to SEQID-00093 SEQID-00094 0.45 98.8 SEQID-00092 0.4289.9 SEQID-00075 0.46 67.9 SEQID-00072 0.46 67.3 SEQID-03712 0.46 66.0SEQID-03763 0.44 50.3 SEQID-03708 0.45 51.6 SEQID-03798 0.46 51.6SEQID-03860 0.45 50.9 SEQID-03651 0.46 50.9

TABLE E1B Expressed Sequences identified as homologs to SEQID-00093SEQID EAA Percent ID to SEQID-00093 SEQID-00074 0.42 91.2 SEQID-000920.42 89.9 SEQID-00075 0.46 66.9 SEQID-00078 0.46 65 SEQID-00106 0.4650.3 SEQID-00104 0.45 50.3 SEQID-00864 0.45 50.3 SEQID-00870 0.45 43.8SEQID-00867 0.47 44.5 SEQID-00105 0.44 41.1 SEQID-00103 0.45 40.5SEQID-00866 0.40 39.8

Example 2 Identification and Selection of Amino Acid Sequences ofNutritive Polypeptides of Edible Species Using cDNA Libraries

Here, nutritive polypeptide amino acid sequences were identified byanalysis of proteins produced from nucleic acid sequences extracted andpurified from edible species.

Construction of cDNA Library.

A library of cDNA from twelve edible species was constructed. The twelveedible species were divided into five categories for RNA extraction.Animal tissues including ground beef, pork, lamb, chicken, turkey, and aportion of tilapia was combined with 50 mg from each edible species.Fruit tissues from grape and tomato including both the skin and thefruit were grounded and combined with 2.5 g from each species. Seeds ofrice and soybean were combined with 1 g from each species and groundedinto powder. 12 ml of Saccharomyces cerevisiae were grown overnight andspun down to obtain 110 mg of wet cell weight of yeast. 1 g of mushroommycelium was grounded and processed using fungi RNA extractionprotocols. All five categories of samples were snap frozen with liquidnitrogen, thawed and lysed using category-specific RNA extractprotocols. The RNA from different food categories was extracted andcombined as one pooled sample. The combined pool of RNA was reversetranscribed into cDNA using oligo-dT as primers resulting in cDNA oflength between 500 bp to 4 kb. Adaptors were ligated to each end of thecDNA and used as PCR primers for amplification of the cDNA library andalso included Sfi I restriction digestion sites for cloning the libraryinto an expression vector. The cDNA library was denatured andre-annealed and the single-stranded DNA was selected using gelelectrophoresis. This process removed extra cDNA from highly abundantRNA species to obtain a normalized cDNA library. The normalized cDNAlibrary was precipitated using ethanol precipitation before PCRamplification and cloning into the expression vectors.

TABLE E2A Primer and adapter sequences flanking  the cDNA. SEQ SequenceAdapter ID (underlined: Sfi I site) 5′ adapter 3910CAGTGGTATCAACGCAGAGTGGCCAT TACGGCCAAGTTACGGG 3′ adapter 3911CAGTGGTATCAACGCAGAGTGGCCGA GGCGGCCTTTTTTTTTTTTTTT

Cloning of cDNA Library into E. coli for Protein Expression.

The cDNA library was cloned into the pET15b backbone vector, which wasamplified with primers with overhangs that contain the correspondingSfiI restriction sites (forward primer overhang:TACGTGTATGKGCCGCCTCGGCC; reverse primer overhang:TACGTGTATGGCCGTAATGG(CC), pET15b contains a pBR322 origin ofreplication, lac-controlled T7 promoter, and a bla gene conferringresistance to carbenicillin. Both the cDNA library and PCR amplifiedbackbone were cut with SfiI. PCR purified, and ligated. The ligationreaction was transformed into 10-Beta High Efficiency Competent Cells(New England Biolabs), and transformed cells were plated onto four LBagar plates containing 100 mg/L carbenicillin. Plates were incubated at37° C. overnight. After colonies had grown, 2 mL of liquid LB medium wasadded to each plate. Cells were scraped into the liquid and mixedtogether, and the suspension was prepared for plasmid extraction to formthe multiplex cDNA plasmid library.

E. coli cDNA Multiplex Expression Methods.

Four strains were used to express the cDNA libraries: T7 Express fromNew England Biolabs: and Rosetta 2(DE3), Rosetta-gami B(DE3), andRosetta-gami 2(DE3) from EMD Millipore. T7 Express is an enhanced BL21derivative which contains the T7 RNA polymerase in the lac operon, whilelacking the Lon and OmpT proteases. The genotype of T7 Express is: fhuA2lacZ::T7 gene1 [Ion] ompT gal sulA11 R(mcr-73::miniTn10-Tet^(S))2 [dcm]R(zgb-210::Tn10-Tet^(S)) endA1 Δ(mcrC-mrr)114::IS10. Rosetta 2(DE3) is aBL21 derivative that supplies tRNAs for 7 rare codons (AGA. AGG, AUA.CUA. GGA, CCC, CGG). The strain is a lysogen of λDE3, and carries the T7RN4 polymerase gene under the lacUV5 promoter. The genotype of Rosetta2(DE3) is: F⁻ ompT hsdS_(B)(r_(B) ⁻m_(B) ⁻) gal dcm (DE3) pRA4RE2(Cam^(R)). Rosetta-gami B(DE3) has the same properties as Rosetta 2(DE3)but includes characteristics that enhance the formation of proteindisulfide bonds in the cytoplasm. The genotype of Rosetta-gami B(DE3) isF⁻ ompT hsdS_(B)(r_(B) ⁻m_(B) ⁻) gal dcm lacY1 ahpC (DE3) gor522:: Tn10trxBpRARE (Cam^(R), Kan^(R). Tet^(R)). Rosetta-gami 2(DE3), similarly toRosetta-gami B(DE3), alleviates codon bias, enhances disulfide bondformation, and have the T7 RNA polymerase gene under the lacUV5 promoterin the chromosome. The genotype of Rosetta-gami 2(DE3) is Δ(ara-leu)7697ΔlacX74 ΔphoA PvuII phoR araD139 ahpC galE galK rpsL(DE3) F′[lac⁺lac^(q) pro] gor522::Tn10 tirB pRARE2 (Cam^(R), Str^(R). Tet^(R))

Roughly 200 ng of prepared cDNA libraries were transformed into the fourbackground strains: T7 Express. Rosetta 2(DE3), Rosetta-gami B(DE3), andRosetta-gami 2(DE3) competent cells. After transforming, 100 μL of eachstrain was plated onto four LB (10 g/l NaCl, 10 g/l tryptone, and 5 g/lyeast extract) 1.5% agar plates containing 100 mg/L carbenicillin andincubated at 37° C. for 16 hrs. After incubation, 2 mL of LB media with100 mg/L carbenicillin was added to the surface of each plate containingseveral thousand transformants, and the cells were suspended in thesurface medium by scraping with a cell spreader and mixing. Suspendedcells from the four replicate plates from each background were combinedto form the pre-inoculum cultures for the expression experiments.

The OD₆₀₀ of the pre-inoculum cultures made from re-suspended cells weremeasured using a plate reader to be between 35 and 40 (T7, Rosetta2(DE3) or 15 and 20 (Rosetta-gami B(DE3) and 2(DE3)). For the fourbackground strains, 125 mL baffled shake flasks containing 10 mL of LBmedium with 100 mg/L carbenicillin were inoculated to OD₆₀₀ 0.2 to formthe inoculum cultures, and incubated at 37° C. shaking at 250 rpm forroughly 6 hours. OD₆₀₀ was measured and the inoculum cultures were usedto inoculate expression cultures in 2 L baffled shake flasks containing250 mL of BioSilta Enbase medium with 100 mg/L carbenicillin, 600 mU/Lof glucoamylase and 0.01% Antifoam 204 to an OD₆₀₀ of 0.1. Cultures wereshaken at 30° C. and 250 rpm for 18 hours, and were induced with 1 mMIPTG and supplemented with additional EnBase media components andanother 600 mU/L of glucoamylase. Heterologous expression was carriedout for 24 hours at 30° C. and 250 rpm, at which point the cultures wereterminated. The terminal cell density was measured and the cells wereharvested by centrifugation (5000×g, 10 min, RT). Cells were stored at−80° C. before being lysed with B-PER (Pierce) according to themanufacturer's protocol. After cell lysis, the whole cell lysate issampled for analysis. In the Rosetta (DE3) strain, the whole cell lysateis centrifuged (3000×g, 10 min RT) and the supernatant is collect as thesoluble fraction of the lysate. Cell lysates were run on SDS-PAGE gels,separated into ten fractions, and then analyzed using MS-MS.

Cloning of cDNA Library into Bacillus for Protein Secretion.

The cDNA library was cloned into the pHT43 vector for protein secretionassay in Bacillus subtilis. The unmodified pHT43 vector from MoBiTeccontains the Pgrac promoter, the SamyQ signal peptide, Amp and Cmresistance genes, a lad region, a repA region, and the ColE1 origin ofreplication. The SamyQ signal peptide was removed. The pHT43 backbonevector with no signal peptide as well as a modified version with theaprE promoter substituted for the grac promoter and with the lacI regionremoved were amplified with primers with overhangs that contain thecorresponding SfiI restriction sites (forward primer overhang:TACGTGTATGGCCGCCTCGGCC; reverse primer overhang:TACGTGTATGGCCGTAATGGCC). Both the cDNA library and the two PCR amplifiedbackbones were cut with SfiI and PCR purified. The cDNA library insertswere ligated into each background. The ligation reactions weretransformed into 10-Beta High Efficiency Competent Cells (New EnglandBiolabs), and cells from each ligation were plated onto four LB agarplates containing 100 mg/L carbenicillin. Plates were incubated at 37°C. overnight. After colonies had grown, 2 mL of liquid LB medium wasadded to each plate. For each ligation, cells were scraped into theliquid and mixed together, and the suspensions were prepped for plasmidextraction to form the multiplex cDNA plasmid libraries (henceforthreferred to as the multiplex (Grac-cDNA and AprE-cDNA libraries).

The expression strains used in this expression experiment are based offof the WB800N strain (MoBiTec). The WB800N strain has the followinggenotype: nprE aprE epr bpr mpr::ble nprB::bsr vpr wprA::hyg cm::neo;NeoR. Strain cDNA-1 contains a mutation that synergizes with the paprEpromoter and has these alterations in addition to the WB800N genotype:pXy1A-comK::Erm, degU32(Hy), sigF::Str. Strain cDNA-2 has thesealterations to WB800N: pXy1A-conK::Erm.

Roughly 1 μg of the multiplex Grac-cDNA library was transformed intoboth Strain cDNA-1 and Strain cDNA-2, and 1 μg of the multiplexAprE-cDNA library was transformed into Strain cDNA-1. Aftertransforming, 100 μL of each strain was plated onto four LB (10 g/lNaCl, 10 g/l tryptone, and 5 g/l yeast extract) 1.5% agar platescontaining 5 mg/L chloramphenicol and incubated at 37° C. for 16 hrs.After incubation, 2 mL of LB media with 5 mg/L chloramphenicol was addedto the surface of each plate containing several thousand transformants,and the cells were suspended in the surface medium by scraping with acell spreader and mixing. Suspended cells from the four replicate platesfrom each transformation were combined to form the preinoculum culturesfor the expression experiments.

The OD₆₀₀ of the preinoculum cultures made from resuspended cells weremeasured using a plate reader to be roughly 20-25. For the three strains(strain cDNA-1+ multiplex Grac-cDNA, strain cDNA-1+ multiplex AprE-cDNA,strain cDNA-2+ Grac-cDNA), 500 nL baffled shake flasks containing 50 mLof 2× Mal medium (20 g/L NaCl, 20 g/L Tryptone, 10 g/L yeast extract, 75μL D-Maltose) with 5 mg/L chloramphenicol were inoculated to OD₆₀₀≈0.2to form the inoculum cultures, and incubated at 30° C. shaking at 250rpm for roughly 6 hours. OD₆₀₀ was measured and the inoculum cultureswere used to inoculate expression cultures in 2 L baffled shake flaskscontaining 2× Mal medium with 5 mg/L chloramphenicol, 1× Teknova TraceMetals, and 0.01% Antifoam 204 to an OD₆₀₀ of 0.1. The strain cDNA-1+multiplex AprE cDNA culture was shaken for 30° C. and 250 rpm for 18hours, at which point the culture was harvested. The terminal celldensity was measured and the cells were harvested by centrifugation(5000×g, 30 min, RT). The strain cDNA-1+ multiplex Grac-cDNA and straincDNA-2+ multiplex Grac-cDNA cultures were shaken at 37° C. and 250 rpmfor 4 hours, and were induced with 1 mM IPTG. Heterologous expressionwas carried out for 4 hours at 37° C. and 250 rpm, at which point thecultures were harvested. Again, the terminal cell density was measuredand the cells were harvested by centrifugation (5000×g, 30 min, RT). Thesupernatant was collected and run on SDS-PAGE gels, separated into tenfractions, and then analyzed using LC-MS/MS to identify secretedproteins.

Mass Spectrometry Analysis.

Whole cell lysate and soluble lysate samples were analyzed for proteinexpression using LC-MS/MS. To analyze samples, 10 μg of sample wasloaded onto a 10% SDS-PAGE gel (Invitrogen) and separated approximately5 cm. The gel was excised into ten segments and the gel slices wereprocessed by washing with 25 mM ammonium bicarbonate, followed byacetonitrile. Gel slices were then reduced with 10 mM dithiothreitol at60° C., followed by alkylation with 50 mM iodoacetamide at roomtemperature. Finally, the samples were digested with trypsin (Promega)at 37° C. for 4 h and the digestions were quenched with the addition offormic acid. The supernatant samples were then analyzed by nano LC/MS/MSwith a Waters NanoAcquity HPLC system interfaced to a ThermoFisher QExactive. Peptides were loaded on a trapping column and eluted over a 75μm analytical column at 350 nL/min; both columns were packed withJupiter Proteo resin (Phenomenex). A 1 h gradient was employed. The massspectrometer was operated in data-dependent mode, with MS and MS/MSperformed in the Orbitrap at 70,000 FWHM resolution and 17,500 FWHMresolution, respectively. The fifteen most abundant ions were selectedfor MS/MS. Data were searched against a database using Mascot toidentify peptides. The database was constructed by combining thecomplete proteome sequences from all twelve species including Bostaurus, Gallus gallus, Vitis vinifera, Ovis aries, Sus scrofa, Oryzasativa, Glycine max, Oreochromis niloticus, Solanum lycopesicum,Agaricus bisporus var bisporus. Saccharomyces cerevisiae, and Meleagrisgallopavo. Mascot DAT files were parsed into the Scaffold software forvalidation, filtering and to create a nonredundant list per sample. Datawere filtered at 1% protein and peptide false discovery rate (FDR) andrequiring at least two unique peptides per protein.

Expressed proteins identified. Mass spectrometry analysis identified atotal of 125 proteins across expression strains. Spectrum counts, whichare related to the protein abundance, are reported to confirm proteinexpression or secretion. Fifty three proteins were identified in wholecell lysate of the Rosetta (DE3) strain, 46 in the soluble fraction ofthe Rosetta (DE3) strain, 36 in Rosetta-Gami B (DE3), 10 in Rosetta-Gami2 (DE3), and 15 in the secreted supernatant of Bacillus subtilis.

The nutritive polypeptides detected in the secreted supernatant ofBacillus subtilis are SEQID-00718, SEQID-00762, SEQID-00763,SEQID-00764, SEQID-00765, SEQID-00766, SEQID-00767, SEQID-00768,SEQID-00769, SEQID-00770, SEQID-00771, SEQID-00772, SEQID-00773,SEQID-00774, SEQID-00775.

The nutritive polypeptides detected in the whole cell lysate of the E.coli Rosetta (DE3) strain are SEQID-00716, SEQID-00718, SEQID-00720,SEQID-00723, SEQID-00724, SEQID-00725, SEQID-00729, SEQID-00732,SEQID-00737, SEQID-00751, SEQID-00776, SEQID-00790, SEQID-00797,SEQID-00798, SEQID-00799, SEQID-00800. SEQID-0080 I, SEQID-00802,SEQID-00803, SEQID-00804, SEQID-00805, SEQID-00806, SEQID-00807,SEQID-00808, SEQID-00809, SEQID-00810, SEQID-00811, SEQID-00812,SEQID-00813, SEQID-00814, SEQID-00815, SEQID-00816, SEQID-00817,SEQID-00818, SEQID-00819, SEQID-00820, SEQID-0082 I, SEQID-00822,SEQID-00823, SEQID-00824, SEQID-00825, SEQID-00826, SEQID-00827,SEQID-00828, SEQID-00829, SEQID-00830, SEQID-00831, SEQID-00832,SEQID-00833, SEQID-00834, SEQID-00835, SEQID-00836. SEQID-00837.

The nutritive polypeptides detected in the soluble lysate of the E. coliRosetta (DE3) strain are SEQID-00716, SEQID-00717, SEQID-00718,SEQID-00719, SEQID-00720, SEQID-00721, SEQID-00722, SEQID-00724,SEQID-00725. SEQID-00726, SEQID-00727, SEQID-00728, SEQID-00729,SEQID-00730, SEQID-00731, SEQID-00732, SEQID-00733, SEQID-00734,SEQID-00735, SEQID-00736, SEQID-00737, SEQID-00738, SEQID-00739.SEQID-00740, SEQID-00741, SEQID-00742, SEQID-00743, SEQID-00744,SEQID-00745. SEQID-00746, SEQID-00747, SEQID-00748, SEQID-00749,SEQID-00750, SEQID-00751, SEQID-00752, SEQID-00753, SEQID-00754,SEQID-00755, SEQID-00756, SEQID-00757, SEQID-00758, SEQID-00759,SEQID-00760, SEQID-00761.

The nutritive polypeptides detected in the E. coli Rosetta-Gami B (DE3)strain are SEQID-00003, SEQID-00004, SEQID-00005, SEQID-00716,SEQID-00718, SEQID-00719. SEQID-00720, SEQID-00729, SEQID-00730,SEQID-00731, SEQID-00732, SEQID-00734. SEQID-00736, SEQID-00740,SEQID-00743, SEQID-00752, SEQID-00760, SEQID-00763, SEQID-00764,SEQID-00776, SEQID-00777, SEQID-00778, SEQID-00779, SEQID-00780,SEQID-00781, SEQID-00782, SEQID-00783, SEQID-00784, SEQID-00785,SEQID-00786, SEQID-00787, SEQID-00788, SEQID-00789, SEQID-00790,SEQID-00791, SEQID-00792.

The nutritive polypeptides detected in the E. coli Rosetta-Gami 2 (DE3)strain are SEQID-00716, SEQID-00737, SEQID-00747, SEQID-00763,SEQID-00789, SEQID-00790. SEQID-00793, SEQID-00794, SEQID-00795,SEQID-00796.

Example 3 Identification and Selection of Amino Acid Sequences ofNutritive Polypeptides of Edible Species Using Annotated ProteinSequence Databases

Construction of Protein Databases. The UniProtKB/Swiss-Prot (acollaboration between the European Bioinformatics Institute and theSwiss Institute of Bioinformatics) is a manually curated and reviewedprotein database, and was used as the starting point for constructing aprotein database. To construct a protein database of edible species, asearch was performed on the UniProt database for proteins from ediblespecies as disclosed in. e.g., PCT/US2013/032232, filed Mar. 15, 2013,PCT/US2013/032180, filed Mar. 15, 2013. PCT/US2013/032225, filed Mar.15, 2013, PCT/US2013/032218, filed Mar. 15, 2013, PCT/US2013/032212,filed Mar. 15, 2013, and PCT/US2013/032206, filed Mar. 15, 2013. Toidentify proteins that are secreted from microorganisms, the UniProtdatabase was searched for species from microorganisms as disclosedherein and proteins that are annotated with keywords or annotations thatincludes secreted, extracellular, cell wall, and outer membrane. Toidentify proteins that are abundant in the human diet, the referenceproteomes of edible species were assembled from genome databases. Asprovided herein, mass spectrometry was performed on proteins extractedfrom each edible species. The peptides identified by mass spectrometrywere mapped to the reference proteomes and the spectrum counts of thepeptides associated with the reference protein sequences were convertedto a measure for the abundance of the corresponding protein in food. Allproteins that were detected above a cutoff spectrum count with highconfidence were assembled into a database. These databases are used foridentifying proteins that are derived from edible species, which aresecreted, and/or are abundant in the human diet.

Processes for Selection of Amino Acid Sequences.

A process for picking a protein or group of proteins can includeidentifying a set of constraints that define the class of protein one isinterested in finding, the database of proteins from which to search,and performing the actual search.

The protein class criteria can be defined by nutritional literature(i.e., what has been previously identified as efficacious), desiredphysiochemical traits (e.g., expressible, soluble, nonallergenic,nontoxic, digestible, etc), and other characteristics. A relevantdatabase of proteins that can be used for searching purposes can bederived from the sequences disclosed herein.

One example of proteins that can be searched is a highly soluble classof proteins for muscle anabolism/immune health/diabetes treatment. Theseproteins are generally solubly expressible, highly soluble uponpurification/isolation, non-allergenic, non-toxic, fast digesting, andmeet some basic nutritional criteria (e.g., [EAA]>0.3, [BCAA]>0.15,[Leucine or Glutamine or Arginine]>0.08, eaa complete).

A search is conducted for expressible, soluble proteins using a binaryclassification model based on two parameters related to thehydrophilicity and hydrophobicity of the protein sequence: solvationscore and aggregation score (see examples below for various descriptionsof these two metrics and measures of efficacy of the model).Alternatively, a search can be conducted for highly charged proteinswith high (or low) net charge per amino acid, which is indicative of anet excess of negative or positive charges per amino acid (see examplebelow for additional description).

The nutritional criteria are satisfied by computing the mass fractionsof all relevant amino acids based on primary sequence. For cases inwhich it is desired to match a known, clinically efficacious amino acidblend a weighted Euclidean distance method can be used (see examplebelow).

As provided herein,allergenicity/toxicity/nonallergenicity/antinutrticity criteria aresearched for using sequence based homology assessments in which eachcandidate sequence is compared to libraries of known allergens, toxins,nonallergens, or antinutritive (e.g., protease inhibitory) proteins (seeexamples herein). In general, cutoffs of <50% global or <35% local (overany given 80aa window) homology (percent ID) can be used for theallergenicity screens, and <35% global for the toxicity andantinutricity screens. In all cases, smaller implies lessallergenic/toxic/antinutritive. The nonallergenicity screen is lesstypically used as a cutoff, but >62% as a cutoff can be used (greaterimplies is more nonallergenic). These screens reduce the list to asmaller subset of proteins enriched in the criteria of interest. Thislist is then ranked using a variety of aggregate objective functions andselections are made from this rank ordered list.

Example 4 Selection of Amino Acid Sequences to Demonstrate Amino AcidPharmacology of Nutritive Polypeptides

Identification of Proteins Enriched in Leucine and Essential Amino Acidsfor the Treatment of Sarcopenia.

As described herein, sarcopenia is the degenerative loss of skeletalmuscle mass (typically 0.5-1% loss per year after the age of 25),quality, and strength associated with aging. Sarcopenia is characterizedfirst by a muscle atrophy (a decrease in the size of the muscle), alongwith a reduction in muscle tissue “quality,” caused by such factors asreplacement of muscle fibres with fat, an increase in fibrosis, changesin muscle metabolism, oxidative stress, and degeneration of theneuromuscular junction. Combined, these changes lead to progressive lossof muscle function and eventually to frailty. It has been shown thatessential amino acid supplementation in elderly, sarcopenia individualscan have an anabolic and/or sparing effect on muscle mass. Furthermore,this supplementation can also translate to improvements in patientstrength and muscle quality. See, e.g., Paddon-Jones D, et al. J ClinEndocrinol Metab 2004, 89:4351-4358; Ferrando, A et al. ClinicalNutrition 2009 1-6; Katsanos C et al. Am J Physiol Endocrinol Metab.2006, 291: 381-387. It has also been shown that the essential amino acidleucine is a particularly important factor in stimulating muscle proteinsynthesis. See, e.g., Borscheim E et al. Am J Physiol Endocrinol Metab2002, 283: E648-E657; Borsheim E et al. Clin Nutr. 2008, 27: 189-95;Esmarck B et al J Physiol 2001, 535: 301-311; Moore D et al. Am J ClinNutr 2009, 89: 161-8). One can identify beneficial nutritivepolypeptides for individuals that suffer from sarcopenia by selectingproteins that are enriched by mass in leucine and the other essentialamino acids.

Using a database of all protein sequences derived from edible species asdescribed herein, candidate sequences that are enriched in leucine (≧15%by mass) and essential amino acids (≧40% by mass) were identified andrank ordered by their total leucine plus essential amino acid massrelative to total amino acid mass. In order to increase the probabilitythat these proteins are solubly expressed, as well as highly soluble atpH 7 with reduced aggregation propensity, solvation score andaggregation score upper bounds of −20 kcal/mol/AA and 0.5 were applied.In order to reduce the likelihood that these proteins would elicit anallergenic response, upper bounds of 50% and 35% were set for the globalallergen homology and allergenicity scores, respectively. In order toreduce the likelihood that these proteins would have toxic effects uponingestion, an upper bound of 35% was set for the toxicity score. Inorder to reduce the likelihood that these proteins would act asinhibitors of digestive proteases, an upper bound of 35% was set for theanti-nutricity score.

An exemplary list of the top 10 nutritive polypeptide sequences that areenriched in leucine (>15% by mass) and essential amino acids (?40% bymass), and meet the afore mentioned cutoffs in solvation score,aggregation score, global allergen homology, allergenicity score,toxicity score, and anti-nutricity score is shown in Table E4A.

TABLE E4A SEQID EAA L SEQID-03552 0.56 0.21 SEQID-03581 0.60 0.15SEQID-03532 0.58 0.16 SEQID-03475 0.56 0.17 SEQID-03499 0.58 0.15SEQID-03494 0.54 0.18 SEQID-03460 0.54 0.17 SEQID-03485 0.54 0.16SEQID-03513 0.54 0.15 SEQID-03491 0.52 0.17

An exemplary list of the top 10 nutritive polypeptide sequences from theexpressed protein database that are enriched in leucine (≧15% by mass)and essential amino acids (≧40% by mass) is shown in Table E4B.

TABLE E4B SEQID EAA L SEQID-00162 0.64 0.34 SEQID-00132 0.60 0.32SEQID-00166 0.65 0.26 SEQID-00169 0.60 0.25 SEQID-00137 0.64 0.20SEQID-00134 0.58 0.24 SEQID-00175 0.63 0.19 SEQID-00194 0.54 0.26SEQID-00193 0.53 0.26 SEQID-00195 0.52 0.26

Example 5 Selection of Amino Acid Sequences of Nutritive PolypeptidesEnriched in Essential Amino Acids and Enriched or Reduced in VariousIndividual Amino Acids of Interest

Using a database of all protein sequences derived from edible species asdescribed herein, candidate sequences enriched in essential amino acidswith elevated or reduced amounts of each amino acid were identified. Inorder to increase the probability that these proteins would be solublyexpressed, as well as highly soluble at pH 7 with reduced aggregationpropensity, solvation score and aggregation score upper bounds of −20kcal/mol/AA and 0.5 were applied. In order to reduce the likelihood thatthese proteins would elicit an allergenic response, upper bounds of 50%and 35% were set for the global allergen homology and allergenicityscores, respectively. In order to reduce the likelihood that theseproteins would have toxic effects upon ingestion, an upper bound of 35%was set for the toxicity score. In order to reduce the likelihood thatthese proteins would act as inhibitors of digestive proteases, an upperbound of 35% was set for the anti-nutricity score. When searching forproteins enriched or reduced in a given amino acid, the cutoffsdescribed above were applied, and proteins were rank ordered by theircalculated amino acid mass fraction of the desired amino acid and thenby their essential amino acid content.

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin alanine that met the above cutoffs in solvation score, aggregationscore, global allergen homology, allergenicity score, toxicity score,and anti-nutricity score is shown in Table E5A. The top 10 nutritivepolypeptide sequences reduced in alanine are shown in Table E5B.

TABLE E5A SEQID EAA A SEQID-03678 0.46 0.18 SEQID-03682 0.44 0.18SEQID-03646 0.46 0.18 SEQID-03653 0.39 0.16 SEQID-03717 0.38 0.16SEQID-03686 0.41 0.15 SEQID-03807 0.46 0.15 SEQID-03864 0.44 0.15SEQID-03663 0.35 0.15 SEQID-03777 0.46 0.14

TABLE E5B SEQID EAA A SEQID-03874 0.62 0.00 SEQID-03552 0.56 0.00SEQID-03880 0.52 0.00 SEQID-03673 0.52 0.00 SEQID-03667 0.50 0.00SEQID-03657 0.50 0.00 SEQID-03842 0.49 0.00 SEQID-03623 0.49 0.00SEQID-03817 0.48 0.00 SEQID-03875 0.48 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin arginine that met the above cutoffs in solvation score, aggregationscore, global allergen homology, allergenicity score, toxicity score,and anti-nutricity score is shown in table ESC. The top 10 nutritivepolypeptide sequences reduced in arginine are shown in Table E5D.

TABLE E5C SEQID EAA R SEQID-03473 0.06 0.72 SEQID-03855 0.09 0.65SEQID-03727 0.10 0.63 SEQID-03767 0.17 0.62 SEQID-03704 0.17 0.60SEQID-03459 0.10 0.60 SEQID-03731 0.16 0.48 SEQID-03698 0.47 0.40SEQID-03687 0.37 0.38 SEQID-03732 0.19 0.38

TABLE E5D SEQID EAA R SEQID-03744 0.60 0.00 SEQID-03770 0.56 0.00SEQID-03880 0.52 0.00 SEQID-03736 0.49 0.00 SEQID-03706 0.49 0.00SEQID-03881 0.49 0.00 SEQID-03668 0.49 0.00 SEQID-03733 0.46 0.00SEQID-03764 0.46 0.00 SEQID-03832 0.44 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin asparagine that met the above cutoffs in solvation score, aggregationscore, global allergen homology, allergenicity score, toxicity score,and anti-nutricity score is shown in table E5E. The top 10 nutritivepolypeptide sequences reduced in asparagine are shown in table E5F.

TABLE E5E SEQID EAA N SEQID-03723 0.39 0.15 SEQID-03721 0.39 0.15SEQID-03803 0.42 0.15 SEQID-03801 0.38 0.15 SEQID-03714 0.40 0.14SEQID-03742 0.41 0.14 SEQID-03724 0.38 0.14 SEQID-03884 0.42 0.14SEQID-03778 0.39 0.13 SEQID-03746 0.41 0.13

TABLE E5F SEQID EAA N SEQID-03874 0.62 0.00 SEQID-03793 0.59 0.00SEQID-03789 0.57 0.00 SEQID-03869 0.57 0.00 SEQID-03809 0.57 0.00SEQID-03662 0.56 0.00 SEQID-03850 0.55 0.00 SEQID-03783 0.55 0.00SEQID-03753 0.54 0.00 SEQID-03677 0.53 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin aspartic acid that met the above cutoffs in solvation score,aggregation score, global allergen homology, allergenicity score,toxicity score, and anti-nutricity score is shown in table E5G. The top10 nutritive polypeptide sequences reduced in aspartic acid are shown intable E5H.

TABLE E5G SEQID EAA D SEQID-03630 0.33 0.28 SEQID-03425 0.34 0.26SEQID-03564 0.33 0.25 SEQID-03543 0.34 0.25 SEQID-03607 0.32 0.24SEQID-03621 0.35 0.23 SEQID-03604 0.37 0.21 SEQID-03827 0.42 0.20SEQID-03540 0.37 0.20 SEQID-03624 0.39 0.19

TABLE E5H SEQID EAA D SEQID-03795 0.62 0.00 SEQID-03468 0.62 0.00SEQID-03672 0.62 0.00 SEQID-03656 0.61 0.00 SEQID-03517 0.60 0.00SEQID-03493 0.60 0.00 SEQID-03816 0.60 0.00 SEQID-03796 0.59 0.00SEQID-03868 0.59 0.00 SEQID-03740 0.59 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin cysteine that met the above cutoffs in solvation score, aggregationscore, global allergen homology, allergenicity score, toxicity score,and anti-nutricity score is shown in table E5I. The top 10 nutritivepolypeptide sequences reduced in cysteine are shown in table E5J.

TABLE E5I SEQID EAA C SEQID-03495 0.24 0.30 SEQID-03514 0.24 0.30SEQID-03571 0.24 0.28 SEQID-03430 0.36 0.27 SEQID-03419 0.37 0.16SEQID-03478 0.29 0.16 SEQID-03523 0.33 0.16 SEQID-03504 0.35 0.16SEQID-03477 0.28 0.16 SEQID-03459 0.10 0.16

TABLE E5J SEQID EAA C SEQID-03636 0.65 0.00 SEQID-03492 0.63 0.00SEQID-03484 0.62 0.00 SEQID-03442 0.61 0.00 SEQID-03417 0.61 0.00SEQID-03563 0.61 0.00 SEQID-03512 0.61 0.00 SEQID-03517 0.60 0.00SEQID-03606 0.60 0.00 SEQID-03493 0.60 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin glutamine that met the above cutoffs in solvation score, aggregationscore, global allergen homology, allergenicity score, toxicity score,and anti-nutricity score is shown in table E5K. The top 10 nutritivepolypeptide sequences reduced in glutamine are shown in table ESL.

TABLE E5K SEQID EAA Q SEQID-03676 0.29 0.19 SEQID-03720 0.29 0.19SEQID-03683 0.33 0.19 SEQID-03782 0.46 0.18 SEQID-03681 0.46 0.18SEQID-03852 0.46 0.18 SEQID-03671 0.43 0.17 SEQID-00515 0.25 0.17SEQID-03866 0.40 0.17 SEQID-03824 0.36 0.16

TABLE E5L SEQID EAA Q SEQID-03636 0.65 0.00 SEQID-03795 0.62 0.00SEQID-03468 0.62 0.00 SEQID-03484 0.62 0.00 SEQID-03570 0.59 0.00SEQID-03422 0.58 0.00 SEQID-03432 0.58 0.00 SEQID-03590 0.58 0.00SEQID-03515 0.58 0.00 SEQID-03499 0.58 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin histidine that met the above cutoffs in solvation score, aggregationscore, global allergen homology, allergenicity score, toxicity score,and anti-nutricity score is shown in table E5M. The top 10 nutritivepolypeptide sequences reduced in histidine are shown in table E5N.

TABLE E5M SEQID EAA H SEQID-03744 0.60 0.25 SEQID-03551 0.48 0.24SEQID-03745 0.56 0.19 SEQID-03793 0.59 0.19 SEQID-03468 0.62 0.15SEQID-03743 0.38 0.13 SEQID-03711 0.56 0.12 SEQID-03847 0.58 0.12SEQID-03637 0.43 0.12 SEQID-03739 0.52 0.12

TABLE E5N SEQID EAA H SEQID-03795 0.62 0.00 SEQID-03874 0.62 0.00SEQID-03656 0.61 0.00 SEQID-03517 0.60 0.00 SEQID-03493 0.60 0.00SEQID-03816 0.60 0.00 SEQID-03796 0.59 0.00 SEQID-03740 0.59 0,00SEQID-03814 0.58 0.00 SEQID-03837 0.57 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin isoleucine that met the above cutoffs in solvation score, aggregationscore, global allergen homology, allergenicity score, toxicity score,and anti-nutricity score is shown in table E50. The top 10 nutritivepolypeptide sequences reduced in isoleucine are shown in table E5P.

TABLE E5O SEQID EAA I SEQID-03722 0.40 0.15 SEQID-03805 0.38 0.15SEQID-03435 0.40 0.15 SEQID-03838 0.42 0.15 5E0ID-03655 0.54 0.15SEQID-03828 0.49 0.15 SEQID-03593 0.39 0.15 SEQID-03818 0.51 0.15SEQID-03841 0.49 0.15 SEQID-03843 0.48 0.14

TABLE E5P SEQID EAA I SEQID-03581 0.60 0.00 SEQID-03685 0.57 0.00SEQID-03705 0.56 0.00 SEQID-03660 0.55 0.00 SEQID-03779 0.53 0.00SEQID-03781 0.52 0.00 SEQID-03647 0.51 0.00 SEQID-03785 0.50 0.00SEQID-03865 0.50 0.00 SEQID-03802 0.49 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin leucine that met the above cutoffs in solvation score, aggregationscore, global allergen homology, allergenicity score, toxicity score,and anti-nutricity score is shown in table E5Q. The top 10 nutritivepolypeptide sequences reduced in leucine are shown in table E5R.

TABLE E5Q SEQID EAA L SEQID-03552 0.56 0.21 SEQID-03428 0.49 0.18SEQID-03623 0.49 0.18 SEQID-03702 0.47 0.18 SEQID-03701 0.49 0.18SEQID-03703 0.49 0.18 SEQID-03599 0.51 0.18 SEQID-03494 0.54 0.18SEQID-03632 0.45 0.18 SEQID-03423 0.44 0.18

TABLE E5R SEQID EAA L SEQID-03661 0.53 0.00 SEQID-03849 0.52 0.00SEQID-03644 0.42 0.00 SEQID-03878 0.39 0.00 SEQID-03652 0.38 0.00SEQID-03419 0.37 0.00 SEQID-03654 0.36 0.00 SEQID-03804 0.36 0.00SEQID-03504 0.35 0.00 SEQID-03477 0.28 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin lysine that met the above cutoffs in solvation score, aggregationscore, global allergen homology, allergenicity score, toxicity score,and anti-nutricity score is shown in table E5S. The top 10 nutritivepolypeptide sequences reduced in lysine are shown in table E5T.

TABLE E5S SEQID EAA K SEQID-03648 0.52 0.36 SEQID-03797 0.56 0.34SEQID-03830 0.52 0.31 SEQID-03829 0.54 0.30 SEQID-03581 0.60 0.30SEQID-03520 0.36 0.30 SEQID-03457 0.37 0.30 SEQID-03471 0.36 0.29SEQID-03859 0.53 0.29 SEQID-03456 0.34 0.29

TABLE E5T SEQID EAA K SEQID-03583 0.42 0.00 SEQID-03684 0.40 0.00SEQID-03813 0.36 0.00 SEQID-03771 0.28 0.00 SEQID-03873 0.26 0.00SEQID-03585 0.25 0.00 SEQID-03704 0.17 0.00 SEQID-03767 0.17 0.00SEQID-03731 0.16 0.00 SEQID-03459 0.10 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin methionine that met the above cutoffs in solvation score, aggregationscore, global allergen homology, allergenicity score, toxicity score,and anti-nutricity score is shown in table E5U. The top 10 nutritivepolypeptide sequences reduced in arginine are shown in table E5V.

TABLE E5U SEQID EAA M SEQID-00552 0.45 0.16 SEQID-03870 0.52 0.15SEQID-03680 0.49 0.15 SEQID-03888 0.39 0.13 SEQID-03738 0.37 0.13SEQID-03698 0.47 0.13 SEQID-03584 0.53 0.12 SEQID-03487 0.53 0.11SEQID-03858 0,49 0.11 SEQID-03787 0.46 0.11

TABLE E5V SEQID EAA M SEQID-03701 0.49 0.00 SEQID-03861 0.49 0.00SEQID-03703 0.49 0.00 SEQID-03702 0.47 0.00 SEQID-03773 0.46 0.00SEQID-03707 0.45 0.00 SEQID-03726 0.41 0.00 SEQID-03725 0.39 0.00SEQID-03734 0.39 0.00 SEQID-03700 0.37 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin phenylalanine that met the above cutoffs in solvation score,aggregation score, global allergen homology, allergenicity score,toxicity score, and anti-nutricity score is shown in table E5W. The top10 nutritive polypeptide sequences reduced in phenylalanine are shown intable E5X.

TABLE E5W SEQID EAA F SEQID-03761 0.48 0.14 SEQID-03831 0.56 0.14SEQID-03836 0.55 0.13 SEQID-03437 0.41 0.13 SEQID-03749 0.41 0.13SEQID-03558 0.44 0.13 SEQID-03791 0.49 0.13 SEQID-03729 0.50 0.12SEQID-03846 0.40 0.12 SEQID-03862 0.50 0.12

TABLE E5X SEQID EAA F SEQID-03581 0.60 0.00 SEQID-03441 0.57 0.00SEQID-03685 0.57 0.00 SEQID-03573 0.55 0.00 SEQID-03661 0.53 0.00SEQID-03859 0.53 0.00 SEQID-03688 0.53 0.00 SEQID-03675 0.53 0.00SEQID-03609 0.53 0.00 SEQID-03584 0.53 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin proline that met the above cutoffs in solvation score, aggregationscore, global allergen homology, allergenicity score, toxicity score,and anti-nutricity score is shown in table E5Y. The top 10 nutritivepolypeptide sequences reduced in proline are shown in table E5Z.

TABLE E5Y SEQID EAA P SEQID-03800 0.33 0.16 SEQID-03756 0.32 0.14SEQID-03839 0.35 0.14 SEQID-03810 0.33 0.13 SEQID-03888 0.39 0.13SEQID-03845 0.41 0.13 SEQID-03834 0.39 0.13 SEQID-03658 0.35 0.13SEQID-03856 0.44 0.12 SEQID-03799 0.37 0.12

TABLE E5Z SEQID EAA P SEQID-03636 0.65 0.00 SEQID-03468 0.62 0.00SEQID-03790 0.57 0.00 SEQID-03486 0.57 0.00 SEQID-03665 0.56 0.00SEQID-03833 0.56 0.00 SEQID-03588 0.56 0.00 SEQID-03808 0.56 0.00SEQID-03719 0.56 0.00 SEQID-03815 0.55 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin serine that met the above cutoffs in solvation score, aggregationscore, global allergen homology, allergenicity score, toxicity score,and anti-nutricity score is shown in table E5AA. The top 10 nutritivepolypeptide sequences reduced in serine are shown in table E5AB.

TABLE E5AA SEQID EAA S SEQID-03747 0.45 0.16 SEQID-03863 0.27 0.15SEQID-03737 0.32 0.15 SEQID-03759 0.40 0.15 SEQID-03882 0.39 0.15SEQID-03748 0.41 0.14 SEQID-03792 0.41 0.14 SEQID-03844 0.37 0.14SEQID-03751 0.47 0.14 SEQID-03822 0.45 0.14

TABLE E5AB SEQID EAA S SEQID-03441 0.57 0.00 SEQID-03867 0.55 0.00SEQID-03645 0.43 0.00 SEQID-03455 0.35 0.00 SEQID-03775 0.30 0.00SEQID-03771 0.28 0.00 SEQID-03772 0.28 0.00 SEQID-03716 0.26 0.00SEQID-03873 0.26 0.00 SEQID-03508 0.41 0.01

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin threonine that met the above cutoffs in solvation score, aggregationscore, global allergen homology, allergenicity score, toxicity score,and anti-nutricity score is shown in table E5AC. The top 10 nutritivepolypeptide sequences reduced in threonine are shown in table E5AD.

TABLE E5AC SEQID EAA T SEQID-03718 0.42 0.16 SEQID-03777 0.46 0.14SEQID-03713 0.42 0.12 SEQID-03871 0.44 0.12 SEQID-03867 0.55 0.12SEQID-03819 0.48 0.12 SEQID-03820 0.41 0.11 SEQID-03653 0.39 0.11SEQID-03717 0.38 0.11 SEQID-03877 0.45 0.11

TABLE E5AD SEQID EAA T SEQID-03744 0.60 0.00 SEQID-03745 0.56 0.00SEQID-03661 0.53 0.00 SEQID-03830 0.52 0.00 SEQID-03849 0.52 0.00SEQID-03887 0.51 0.00 SEQID-03886 0.50 0.00 SEQID-03670 0.48 0.00SEQID-03551 0.48 0.00 SEQID-03780 0.47 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin tryptophan that met the above cutoffs in solvation score, aggregationscore, global allergen homology, allergenicity score, toxicity score,and anti-nutricity score is shown in table E5AE. The top 10 nutritivepolypeptide sequences reduced in tryptophan are shown in table E5AF.

TABLE E5AE SEQID EAA W SEQID-03583 0.42 0.15 SEQID-03635 0.40 0.13SEQID-03555 0.50 0.11 SEQID-03679 0.48 0.09 SEQID-03440 0.44 0.09SEQID-03439 0.45 0.09 SEQID-03468 0.62 0.08 SEQID-01546 0.51 0.08SEQID-03576 0.42 0.08 SEQID-03821 0.44 0.08

TABLE E5AF SEQID EAA W SEQID-03672 0.62 0.00 SEQID-03512 0.61 0.00SEQID-03606 0.60 0.00 SEQID-03744 0.60 0.00 SEQID-03581 0.60 0.00SEQID-03868 0.59 0.00 SEQID-03762 0.59 0.00 SEQID-03857 0.59 0.00SEQID-03793 0.59 0.00 SEQID-03769 0.59 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin tyrosine that met the above cutoffs in solvation score, aggregationscore, global allergen homology, allergenicity score, toxicity score,and anti-nutricity score is shown in table E5AG. The top 10 nutritivepolypeptide sequences reduced in tyrosine are shown in table E5AH.

TABLE E5AG SEQID EAA Y SEQID-03848 0.32 0.16 SEQID-03831 0.56 0.15SEQID-03876 0.26 0.15 SEQID-00325 0.42 0.14 SEQID-03794 0.43 0.14SEQID-03826 0.38 0.14 SEQID-03659 0.46 0.14 SEQID-03786 0.35 0.14SEQID-03784 0.38 0.14 SEQID-03823 0.39 0.14

TABLE ESAH SEQID EAA Y SEQID-03468 0.62 0.00 SEQID-03442 0.61 0.00SEQID-03417 0.61 0.00 SEQID-03563 0.61 0.00 SEQID-03606 0.60 0.00SEQID-03469 0.60 0.00 SEQID-03443 0.60 0.00 SEQID-03581 0.60 0.00SEQID-03796 0.59 0.00 SEQID-03762 0.59 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin valine that met the above cutoffs in solvation score, aggregationscore, global allergen homology, allergenicity score, toxicity score,and anti-nutricity score is shown in table E5AI. The top 10 nutritivepolypeptide sequences reduced in valine are shown in table E5AJ.

TABLE E5AI SEQID EAA V SEQID-03881 0.49 0.17 SEQID-03790 0.57 0.17SEQID-03808 0.56 0.17 SEQID-03606 0.60 0.17 SEQID-03688 0.53 0.16SEQID-03806 0.55 0.16 SEQID-03643 0.51 0.15 SEQID-03788 0.58 0.14SEQID-03762 0.59 0.14 SEQID-03674 0.51 0.14

TABLE E5AJ SEQID EAA V SEQID-03879 0.56 0.00 SEQID-03552 0.56 0.00SEQID-03835 0.54 0.00 SEQID-03851 0.53 0.00 SEQID-03757 0.53 0.00SEQID-03648 0.52 0.00 SEQID-03766 0.50 0.00 SEQID-03710 0.46 0.00SEQID-03764 0.46 0.00 SEQID-00552 0.45 0.00

Selection of Expressed Proteins Enriched Essential Amino Acids andEnriched or Reduced in Various Individual Amino Acids.

Using the database of all expressed protein sequences described herein,candidate sequences enriched in essential amino acids with elevated orreduced amounts of each amino acid were identified. When searching forproteins enriched or reduced in a given amino acid, proteins were rankordered by their calculated amino acid mass fraction of the desiredamino acid and then by their essential amino acid content.

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin alanine is shown in table E5AK. The top 10 nutritive polypeptidesequences reduced in alanine are shown in table E5AL.

TABLE E5AK SEQID EAA A SEQID-00499 0.34 0.18 SEQID-00512 0.44 0.17SEQID-00651 0.39 0.17 SEQID-00519 0.38 0.16 SEQID-02704 0.42 0.16SEQID-02703 0.42 0.13 SEQID-00530 0.37 0.13 SEQID-00544 0.45 0.12SEQID-00549 0.40 0.12 SEQID-02675 0.50 0.11

TABLE E5AL SEQID EAA A SEQID-00140 0.70 0.00 SEQID-00057 0.41 0.00SEQID-00652 0.28 0.00 SEQID-00199 0.52 0.00 SEQID-00198 0.53 0.00SEQID-00197 0.52 0.00 SEQID-00196 0.53 0.00 SEQID-00722 0.53 0.01SEQID-00204 0.51 0.01 SEQID-00203 0.51 0.01

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin arginine is shown in table E5AM. The top 10 nutritive polypeptidesequences reduced in arginine are shown in table E5AN.

TABLE E5AM SEQID EAA R SEQID-00540 0.41 0.23 SEQID-00567 0.42 0.22SEQID-00636 0.47 0.22 SEQID-00556 0.33 0.22 SEQID-00637 0.42 0.22SEQID-00575 0.33 0.22 SEQID-00492 0.42 0.21 SEQID-00631 0.38 0.21SEQID-00551 0.41 0.21 SEQID-00328 0.45 0.20

TABLE E5AN SEQID EAA R SEQID-00140 0.70 0.00 SEQID-00146 0.67 0.00SEQID-00150 0.67 0.00 SEQID-00143 0.65 0.00 SEQID-00525 0.64 0.00SEQID-00162 0.64 0.00 SEQID-00175 0.63 0.00 SEQID-00169 0.60 0.00SEQID-00548 0.59 0.00 SEQID-00536 0.58 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin asparagine is shown in table E5AO. The top 10 nutritive polypeptidesequences reduced in asparagine are shown in table E5AP.

TABLE E5AO SEQID EAA N SEQID-00195 0.52 0.14 SEQID-00194 0.54 0.14SEQID-00193 0.53 0.12 SEQID-03872 0.47 0.12 SEQID-01388 0.36 0.12SEQID-00552 0.45 0.12 SEQID-00169 0.60 0.11 SEQID-00196 0.53 0.10SEQID-00197 0.52 0.10 SEQID-03693 0.34 0.10

TABLE E5AP SEQID EAA N SEQID-00536 0.58 0.00 SEQID-00284 0.54 0.00SEQID-00212 0.51 0.00 SEQID-00101 0.51 0.00 SEQID-00219 0.50 0.00SEQID-00634 0.50 0.00 SEQID-00624 0.49 0.00 SEQID-00639 0.46 0.00SEQID-00597 0.45 0.00 SEQID-00527 0.40 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin aspartic acid is shown in table E5AQ. The top 10 nutritivepolypeptide sequences reduced in aspartic acid are shown in table E5AR.

TABLE E5AQ SEQID EAA D SEQID-00562 0.40 0.19 SEQID-03853 0.34 0.17SEQID-00116 0.32 0.16 SEQID-00102 0.45 0.16 SEQID-00115 0.32 0.16SEQID-00484 0.38 0.16 SEQID-00100 0.46 0.15 SEQID-00220 0.52 0.15SEQID-00098 0.50 0.15 SEQID-00078 0.46 0.14

TABLE E5AR SEQID EAA D SEQID-00166 0.65 0.00 SEQID-00051 0.59 0.00SEQID-00052 0.59 0.00 SEQID-00053 0.57 0.00 SEQID-00054 0.55 0.00SEQID-00055 0.55 0.00 SEQID-00523 0.51 0.00 SEQID-00635 0.46 0.00SEQID-00230 0.45 0.00 SEQID-00637 0.42 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin cysteine is shown in table E5AS. The top 10 nutritive polypeptidesequences reduced in cysteine are shown in table E5AT.

TABLE E5AS SEQID EAA C SEQID-00737 0.28 0.18 SEQID-00652 0.28 0.16SEQID-00007 0.28 0.13 SEQID-00007 0.28 0.13 SEQID-00558 0.36 0.13SEQID-00013 0.28 0.12 SEQID-00014 0.30 0.12 SEQID-00989 0.34 0.12SEQID-00566 0.38 0.11 SEQID-00596 0.44 0.11

TABLE E5AT SEQID EAA C SEQID-00166 0.65 0.00 SEQID-00137 0.64 0.00SEQID-00525 0.64 0.00 SEQID-00162 0.64 0.00 SEQID-03297 0.62 0.00SEQID-00169 0.60 0.00 SEQID-00132 0.60 0.00 SEQID-00298 0.59 0.00SEQID-00536 0.58 0.00 SEQID-00297 0.58 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin glutamine is shown in table ESAU. The top 10 nutritive polypeptidesequences reduced in glutamine are shown in table E5AV.

TABLE E5AU SEQID EAA Q SEQID-00743 0.29 0.22 SEQID-00513 0.33 0.17SEQID-03695 0.38 0.17 SEQID-00522 0.40 0.17 SEQID-00515 0.25 0.17SEQID-03692 0.44 0.14 SEQID-03666 0.35 0.13 SEQID-00613 0.36 0.13SEQID-00585 0.44 0.13 SEQID-00223 0.50 0.13

TABLE E5AV SEQID EAA Q SEQID-00143 0.65 0.00 SEQID-00137 0.64 0.00SEQID-00525 0.64 0.00 SEQID-00134 0.58 0.00 SEQID-00194 0.54 0.00SEQID-00193 0.53 0.00 SEQID-00195 0.52 0.00 SEQID-00650 0.50 0.00SEQID-00563 0.50 0.00 SEQID-00598 0.49 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin histidine is shown in table E5AW. The top 10 nutritive polypeptidesequences reduced in histidine are shown in table E5AX.

TABLE E5AW SEQID EAA H SEQID-00536 0.58 0.23 SEQID-00560 0.55 0.18SEQID-01162 0.48 0.12 SEQID-00585 0.44 0.10 SEQID-00298 0.59 0.10SEQID-00615 0.40 0.10 SEQID-00525 0.64 0.10 SEQID-00297 0.58 0.10SEQID-00764 0.56 0.09 SEQID-00128 0.53 0.08

TABLE E5AX SEQID EAA H SEQID-00043 0.57 0.00 SEQID-00531 0.55 0.00SEQID-00592 0.53 0.00 SEQID-00224 0.53 0.00 SEQID-00024 0.52 0.00SEQID-00625 0.52 0.00 SEQID-00233 0.52 0.00 SEQID-00587 0.51 0.00SEQID-00213 0.51 0.00 SEQID-00214 0.51 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin isoleucine is shown in table E5AY. The top 10 nutritive polypeptidesequences reduced in isoleucine are shown in table E5AZ.

TABLE E5AY SEQID EAA I SEQID-00561 0.68 0.18 SEQID-00134 0.58 0.14SEQID-00175 0.63 0.14 SEQID-00162 0.64 0.14 SEQID-00234 0.51 0.13SEQID-00233 0.52 0.13 SEQID-00169 0.60 0.13 SEQID-00025 0.48 0.13SEQID-00043 0.57 0.12 SEQID-00584 0.50 0.12

TABLE E5AZ SEQID EAA I SEQID-00762 0.56 0.00 SEQID-00764 0.56 0.00SEQID-00571 0.54 0.00 SEQID-00212 0.51 0.00 SEQID-00237 0.48 0.00SEQID-00236 0.45 0.00 SEQID-00551 0.41 0.00 SEQID-00515 0.25 0.01SEQID-00128 0.53 0.01 SEQID-00651 0.39 0.01

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin leucine is shown in table E5BA. The top 10 nutritive polypeptidesequences reduced in leucine are shown in table E5BB.

TABLE E5BA SEQID EAA L SEQID-00162 0.64 0.34 SEQID-00132 0.60 0.32SEQID-00195 0.52 0.26 SEQID-00194 0.54 0.76 SEQID-00193 0.53 0.26SEQID-00166 0.65 0.26 SEQID-00169 0.60 0.25 SEQID-00134 0.58 0.24SEQID-00212 0.51 0.23 SEQID-00139 0.49 0.23

TABLE E5BB SEQID EAA L SEQID-00553 0.39 0.00 SEQID-00743 0.29 0.00SEQID-00522 0.40 0.01 SEQID-00554 0.38 0.01 SEQID-00585 0.44 0.01SEQID-00560 0.55 0.01 SEQID-00529 0.38 0.01 SEQID-00552 0.45 0.01SEQID-00547 0.49 0.01 SEQID-00575 0.33 0.01

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin lysine is shown in table E5BC. The top 10 nutritive polypeptidesequences reduced in lysine are shown in table E5BD.

TABLE E5BC SEQID EAA K SEQID-00560 0.55 0.25 SEQID-00573 0.54 0.23SEQID-00619 0.51 0.23 SEQID-00553 0.39 0.23 SEQID-00572 0.54 0.23SEQID-00623 0.54 0.23 SEQID-03691 0.52 0.23 SEQID-00503 0.49 0.22SEQID-00564 0.51 0.22 SEQID-00517 0.49 0.22

TABLE E5BD SEQID EAA K SEQID-00166 0.65 0.00 SEQID-00175 0.63 0.00SEQID-00169 0.60 0.00 SEQID-00134 0.58 0.00 SEQID-00535 0.30 0.00SEQID-00513 0.33 0.01 SEQID-02675 0.50 0.01 SEQID-00490 0.58 0.01SEQID-00512 0.44 0.01 SEQID-00500 0.40 0.01

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin methionine is shown in table E5BE. The top 10 nutritive polypeptidesequences reduced in arginine are shown in table E5BF.

TABLE E5BE SEQID EAA M SEQID-00552 0.45 0.16 SEQID-00513 0.33 0.13SEQID-00529 0.38 0.09 SEQID-00526 0.41 0.09 SEQID-00868 0.48 0.09SEQID-00595 0.44 0.09 SEQID-00584 0.50 0.09 SEQID-00486 0.56 0.09SEQID-00092 0.42 0.08 SEQID-00074 0.42 0.08

TABLE E5BF SEQID EAA M SEQID-00132 0.60 0.00 SEQID-00051 0.59 0.00SEQID-00052 0.59 0.00 SEQID-00043 0.57 0.00 SEQID-00053 0.57 0.00SEQID-00055 0.55 0.00 SEQID-00054 0.55 0.00 SEQID-00224 0.53 0.00SEQID-00024 0.52 0.00 SEQID-00220 0.52 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin phenylalanine is shown in table E5BG. The top 10 nutritivepolypeptide sequences reduced in phenylalanine are shown in table E5BH.

TABLE E5BG SEQID EAA F SEQID-00150 0.67 0.13 SEQID-00595 0.44 0.13SEQID-00561 0.68 0.13 SEQID-00118 0.51 0.12 SEQID-00597 0.45 0.12SEQID-00507 0.51 0.12 SEQID-00594 0.44 0.12 SEQID-00501 0.50 0.12SEQID-00175 0.63 0.11 SEQID-00485 0.46 0.11

TABLE E5BH SEQID EAA F SEQID-00162 0.64 0.00 SEQID-00560 0.55 0.00SEQID-00224 0.53 0.00 SEQID-00220 0.52 0.00 SEQID-00195 0.52 0.00SEQID-00241 0.52 0.00 SEQID-00215 0.51 0.00 SEQID-00213 0.51 0.00SEQID-00214 0.51 0.00 SEQID-00212 0.51 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin proline is shown in table E5BT. The top 10 nutritive polypeptidesequences reduced in proline are shown in table E5BJ.

TABLE E5BI SEQID EAA P SEQID-00743 0.29 0.28 SEQID-00553 0.39 0.24SEQID-03641 0.24 0.20 SEQID-03444 0.23 0.16 SEQID-00169 0.60 0.14SEQID-00005 0.48 0.14 SEQID-00805 0.50 0.13 SEQID-00737 0.28 0.13SEQID-03451 0.40 0.11 SEQID-03447 0.30 0.10

TABLE E5BJ SEQID EAA P SEQID-00150 0.67 0.00 SEQID-00137 0.64 0.00SEQID-00287 0.59 0.00 SEQID-00548 0.59 0.00 SEQID-00142 0.56 0.00SEQID-00560 0.55 0.00 SEQID-00224 0.53 0.00 SEQID-00220 0.52 0.00SEQID-00241 0.52 0.00 SEQID-00216 0.52 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin serine is shown in table E5BK. The top 10 nutritive polypeptidesequences reduced in serine are shown in table E5BL.

TABLE E5BK SEQID EAA S SEQID-03447 0.30 0.27 SEQID-00483 0.42 0.16SEQID-00535 0.30 0.16 SEQID-00630 0.35 0.14 SEQID-00134 0.58 0.14SEQID-00557 0.47 0.13 SEQID-03760 0.39 0.12 SEQID-03642 0.37 0.12SEQID-00652 0.28 0.12 SEQID-00577 0.47 0.12

TABLE E5BL SEQID EAA S SEQID-00175 0.63 0.00 SEQID-00051 0.59 0.00SEQID-00052 0.59 0.00 SEQID-00536 0.58 0.00 SEQID-00043 0.57 0.00SEQID-00053 0.57 0.00 SEQID-00643 0.57 0.00 SEQID-00055 0.55 0.00SEQID-00054 0.55 0.00 SEQID-00112 0.50 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin threonine is shown in table E5BM. The top 10 nutritive polypeptidesequences reduced in threonine are shown in table E5BN.

TABLE E5BM SEQID EAA T SEQID-00404 0.49 0.14 SEQID-00547 0.49 0.13SEQID-00522 0.40 0.13 SEQID-00569 0.56 0.13 SEQID-00528 0.53 0.11SEQID-00504 0.47 0.11 SEQID-03768 0.42 0.11 SEQID-00523 0.51 0.11SEQID-03649 0.49 0.11 SEQID-00116 0.32 0.11

TABLE E5BN SEQID EAA T SEQID-00560 0.55 0.00 SEQID-00057 0.41 0.00SEQID-00542 0.41 0.00 SEQID-00059 0.41 0.00 SEQID-00015 0.30 0.00SEQID-00014 0.30 0.00 SEQID-00013 0.28 0.00 SEQID-00007 0.28 0.00SEQID-00007 0.28 0.00 SEQID-00621 0.39 0.01

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin tryptophan is shown in table E5BM. The top 10 nutritive polypeptidesequences reduced in tryptophan are shown in table E5BN.

TABLE E5BM SEQID EAA W SEQID-01546 0.51 0.08 SEQID-00642 0.45 0.08SEQID-03690 0.43 0.08 SEQID-03776 0.43 0.08 SEQID-03297 0.62 0.07SEQID-03244 0.46 0.07 SEQID-00512 0.44 0.07 SEQID-00814 0.42 0.07SEQID-00110 0.49 0.06 SEQID-03137 0.50 0.06

TABLE E5BN SEQID EAA W SEQID-00166 0.65 0.00 SEQID-00137 0.64 0.00SEQID-00525 0.64 0.00 SEQID-00162 0.64 0.00 SEQID-00169 0.60 0.00SEQID-00051 0.59 0.00 SEQID-00052 0.59 0.00 SEQID-00134 0.58 0.00SEQID-00536 0.58 0.00 SEQID-00043 0.57 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin tyrosine is shown in table E5BO. The top 10 nutritive polypeptidesequences reduced in tyrosine are shown in table E5BP.

TABLE E5BO SEQID EAA Y SEQID-00013 0.28 0.16 SEQID-00007 0.28 0.15SEQID-00007 0.28 0.15 SEQID-00015 0.30 0.14 SEQID-00325 0.42 0.14SEQID-00014 0.30 0.13 SEQID-00513 0.33 0.12 SEQID-03689 0.41 0.11SEQID-00521 0.41 0.11 SEQID-00640 0.47 0.11

TABLE E5BP SEQID EAA V SEQID-00140 0.70 0.00 SEQID-00146 0.67 0.00SEQID-00051 0.59 0.00 SEQID-00052 0.59 0.00 SEQID-00548 0.59 0.00SEQID-00134 0.58 0.00 SEQID-00043 0.57 0.00 SEQID-00053 0.57 0.00SEQID-00054 0.55 0.00 SEQID-00055 0.55 0.00

An exemplary list of the top 10 nutritive polypeptide sequences enrichedin valine is shown in table E5BQ. The top 10 nutritive polypeptidesequences reduced in valine are shown in table E5BR.

TABLE E5BQ SEQID EAA V SEQID-00550 0.49 0.18 SEQID-00592 0.53 0.16SEQID-00532 0.44 0.15 SEQID-00620 0.50 0.15 SEQID-00644 0.42 0.14SEQID-00514 0.46 0.13 SEQID-00518 0.52 0.13 SEQID-00598 0.49 0.13SEQID-00581 0.51 0.13 SEQID-00145 0.51 0.13

TABLE E5BR SEQID EAA V SEQID-00239 0.48 0.00 SEQID-00552 0.45 0.00SEQID-00240 0.45 0.00 SEQID-00615 0.40 0.00 SEQID-00652 0.28 0.00SEQID-00515 0.25 0.01 SEQID-00522 0.40 0.01 SEQID-00560 0.55 0.01SEQID-00645 0.56 0.01 SEQID-00647 0.42 0.01

Example 6 Selection of Amino Acid Sequences of Nutritive PolypeptidesEnriched in Essential Amino Acids to Provide Protein Nutrition and forthe Treatment of Protein Malnutrition

It has been shown that humans cannot endogenously synthesize nine of thetwenty naturally occurring amino acids: histidine, leucine, isoleucine,valine, phenylalanine, methionine, threonine, lysine, and tryptophan(Young, V. R. and Tharakan, J. F. Nutritional essentiality of aminoacids and amino acid requirements in healthy adults. In Metabolic andTherapeutic Aspects of Amino Acids in Clinical Nutrition. SecondEdition. Cynober, L. A. Ed.; CRC Press: New York, 2004; pp 439-470). Assuch, there is a need to ingest sufficient quantities of these nineessential amino acids to avoid protein malnutrition and the deleterioushealth effects that result from this state. Nutritive polypeptides areidentified that are useful for the fulfillment of these essential aminoacid requirements either in healthy or malnourished individuals byselecting those that are enriched in essential amino acids by mass andcontain a non-zero amount of each essential amino acid (i.e., thenutritive polypeptide sequence is essential amino acid complete).

Using a database of all protein sequences derived from edible species asdescribed herein, candidate sequences that are essential amino acidcomplete and enriched in essential amino acids were identified. In orderto increase the probability of these proteins being solubly expressedand highly soluble at pH 7 with reduced aggregation propensity,solvation score and aggregation score upper bounds of −20 kcal/mol/AAand 0.5 were applied. In order to reduce the likelihood that theseproteins would elicit an allergenic response, upper bounds of 50% and35% were set for the global allergen homology and allergenicity scores,respectively. In order to reduce the likelihood that these proteinswould have toxic effects upon ingestion, an upper bound of 35% was setfor the toxicity score. In order to reduce the likelihood that theseproteins would act as inhibitors of digestive proteases, an upper boundof 35% was set for the anti-nutricity score.

An exemplary list of the top 10 nutritive polypeptide sequences that areessential amino acid complete, enriched in essential amino acids, andmeet the aforementioned cutoffs in solvation score, aggregation score,global allergen homology, allergenicity score, toxicity score, andanti-nutricity score is shown in table E6A.

TABLE E6A SEQID EAAc EAA SEQID-03636 1 0.65 SEQID-03492 1 0.63SEQID-03468 1 0.62 SEQID-03544 1 0.62 SEQID-03484 1 0.62 SEQID-03442 10.61 SEQID-03417 1 0.61 SEQID-03563 1 0.61 SEQID-03469 1 0.60SEQID-03443 1 0.60

An exemplary list of the top 10 nutritive polypeptide sequences from theexpressed protein database that are essential amino acid complete andenriched in essential amino acids is shown in table E6B.

TABLE E6B SEQID EAAc EAA SEQID-00140 1 0.70 5EQID-00561 1 0.68SEQID-00146 1 0.67 SEQID-00150 1 0.67 SEQID-00143 I 0.65 SEQID-03297 10.62 SEQID-00487 I 0.61 SEQID-00287 1 0.59 SEQID-00298 1 0.59SEQID-00548 1 0.59

Example 7 Selection of Amino Acid Sequences of Nutritive PolypeptidesEnriched in Branched Chain Amino Acids for Muscle Health, and Selectionof Amino Acid Sequences of Nutritive Polypeptides Reduced in BranchedChain Amino Acids for Treatment of Diabetes, Cardiovascular Disease,Chronic Kidney Disease and Stroke

Identification of Proteins Enriched in Branched Chain Amino Acids forthe Treatment of Hepatic and/or Renal Disease.

Using a database of all protein sequences derived from edible species asdescribed herein, candidate sequences that are enriched or reduced inbranched chain amino acids were identified. In order to increase theprobability that these proteins are solubly expressed, as well as highlysoluble at pH 7 with reduced aggregation propensity, solvation score andaggregation score upper bounds of −20 kcal/mol/AA and 0.5 were applied.In order to reduce the likelihood that these proteins would elicit anallergenic response, upper bounds of 50% and 35% were set for the globalallergen homology and allergenicity scores, respectively. In order toreduce the likelihood that these proteins would have toxic effects uponingestion, an upper bound of 35% was set for the toxicity score. Inorder to reduce the likelihood that these proteins would act asinhibitors of digestive proteases, an upper bound of 35% was set for theanti-nutricity score.

An exemplary list of the top 10 nutritive polypeptide sequences that areenriched in branched chain amino acids, and meet the afore mentionedcutoffs in solvation score, aggregation score, global allergen homology,allergenicity score, toxicity score, and anti-nutricity score is shownin table E7A.

TABLE E7A SEQID EAA BCAA SEQID-03532 0.58 0.31 SEQID-03616 0.53 0.31SEQID-03629 0.56 0.31 SEQID-03619 0.52 0.29 SEQID-03542 0.49 0.29SEQID-03519 0.49 0.29 SEQID-03603 0.53 0.29 SEQID-03536 0.52 0.29SEQID-03597 0.48 0.29 SEQID-03623 0.49 0.29

An exemplary list of the top 10 nutritive polypeptide sequences from theexpressed protein database that are enriched in branched chain aminoacids is shown in table E7B.

TABLE E7B SEQID EAA BCAA SEQID-00162 0.64 0.53 SEQID-00166 0.65 0.46SEQID-00134 0.58 0.46 SEQID-00169 0.60 0.43 SEQID-00043 0.57 0.41SEQID-00132 0.60 0.41 SEQID-00137 0.64 0.39 SEQID-00175 0.63 0.38SEQID-00550 0.49 0.38 SEQID-00234 0.51 0.37

An exemplary list of the top 10 nutritive polypeptide sequences that arereduced in branched chain amino acids, and meet the afore mentionedcutoffs in solvation score, aggregation score, global allergen homology,allergenicity score, toxicity score, and anti-nutricity score is shownin table E7C.

TABLE E7C SEQID EAA BCAA SEQID-03471 0.36 0.01 SEQID-03473 0.06 0.01SEQID-03571 0.24 0.01 SEQID-03495 0.24 0.01 SEQID-03514 0.24 0.01SEQID-00552 0.45 0.03 5EQID-03611 0.37 0.03 SEQID-03457 0.37 0.03SEQID-03456 0.34 0.03 SEQID-03520 0.36 0.03

An exemplary list of the top 10 nutritive polypeptide sequences from theexpressed protein database that are reduced in branched chain aminoacids is shown in table E7D.

TABLE E7D SEQID EAA BCAA SEQID-00552 0.45 0.03 SEQID-00522 0.40 0.03SEQID-00515 0.25 0.05 SEQID-00553 0.39 0.05 SEQID-00585 0.44 0.06SEQID-00637 0.42 0.07 SEQID-00652 0.28 0.08 SEQID-00615 0.40 0.08SEQID-00743 0.29 0.08 SEQID-00547 0.49 0.09

Example 8 Selection of Amino Acid Sequences of Nutritive PolypeptidesHaving Low or No Phenylalanine and Enriched in Tyrosine and all OtherEssential Amino Acids for Treatment or Prevention of Phenylketonuria

Individuals who suffer from phenylketonuria (PKU) are unable to processthe amino acid phenylalanine and catalyze its conversion to tyrosineoften due to a malfunctioning hepatic enzyme phenylalnine hydroxylase(MacLeod E. L. and Ney D. M. Nutritional Management of Phenylketonuria.Annales Nestle. (2010) 68:58-69). In these individuals, when proteincontaining the amino acid phenylalanine is ingested, phenylalanineaccumulates in the blood. Untreated PKU has serious untoward healtheffects, including impaired school performance, impaired executivefunctioning, and long term intellectual disability (Matalon, R.,Michals-Matalon. K., Bhatia, G., Grechanina, E., Novikov, P., McDonald,J. D., Grady, J., Tyring, S. K., Guttler, F. Large neutral amino acidsin the treatment of phenylketonuria. J. Inherit. Metab. Dis. (2006) 29:732-738). One way phenylalanine blood levels can be kept low to avoidneurological effects is to avoid the ingestion of phenylalaninecontaining proteins and/or only consume protein sources that are low inphenylalanine. As basic protein nutritional requirements of all otheramino acids must also be met, sufficient intake of the other essentialamino acids (histidine, leucine, isoleucine, valine, methionine,threonine, lysine, and tryptophan) and tyrosine, which becomesconditionally essential in these individuals, is required. One canidentify beneficial nutritive polypeptides for individuals that sufferfrom phenylketonuria by selecting proteins that contain low or nophenylalanine and are enriched by mass in tyrosine and the otheressential amino acids.

Using a database of all protein sequences derived from edible species asdescribed herein, candidate sequences that contain low or nophenylalanine by mass, are essential amino acid and tyrosine complete(aside from phenylalanine), and enriched in tyrosine and essential aminoacids were identified and rank ordered first by their phenylalanine massfraction and then by their total tyrosine plus essential amino acid massfraction. In order to increase the probability that these proteins aresolubly expressed, as well as highly soluble at pH 7 with reducedaggregation propensity, solvation score and aggregation score upperbounds of −20 kcal/mol/AA and 0.5 were applied. In order to reduce thelikelihood that these proteins would elicit an allergenic response,upper bounds of 50% and 35% were set for the global allergen homologyand allergenicity scores, respectively. In order to reduce thelikelihood that these proteins would have toxic effects upon ingestion,an upper bound of 35% was set for the toxicity score. In order to reducethe likelihood that these proteins would act as inhibitors of digestiveproteases, an upper bound of 35% was set for the anti-nutricity score.

An exemplary list of the top 10 nutritive polypeptide sequences thatcontain low or no phenylalanine by mass, are essential amino acid andtyrosine complete (aside from phenylalanine), enriched in tyrosine andessential amino acids, and meet the afore mentioned cutoffs in solvationscore, aggregation score, global allergen homology, allergenicity score,toxicity score, and anti-nutricity score is shown in table E8A.

TABLE E8A SEQID EAA F Y SEQID-03584 0.53 0.00 0.09 SEOID-03479 0.52 0.000.04 SEQID-03573 0.55 0.00 0.01 SEQID-00634 0.50 0.00 0.05 SEQID-034660.49 0.00 0.05 SEOID-03609 0.53 0.00 0.01 SEQID-03498 0.45 0.00 0.06SEQID-03465 0.40 0.00 0.08 SEQID-03587 0.46 0.00 0.01 SEQID-03463 0.410.00 0.05An exemplary list of the top 10 nutritive polypeptide sequences from theexpressed protein database that contain low or no phenylalanine by mass,are essential amino acid and tyrosine complete (aside fromphenylalanine), and enriched in tyrosine and essential amino acids isshown in table E8B.

TABLE E8B SEQID EAA F Y SEQID-00634 0.50 0.00 0.05 SEQID-00514 0.46 0.010.01 SEQID-00329 0.47 0.01 0.03 SEQID-00628 0.51 0.01 0.02 SEQID-006360.47 0.01 0.04 SEQID-03634 0.45 0.01 0.04 SEQID-00335 0.38 0.01 0.07SEQID-00639 0.46 0.01 0.06 SEQID-03448 0.40 0.01 0.03 SEQID-03889 0.420.02 0.01

Example 9 Selection of Amino Acid Sequences of Nutritive PolypeptidesContaining Fragments or Regions of Naturally-Occurring ProteinSequences: Nutritive Polypeptide Fragments Enriched in Leucine and allEssential Amino Acids

In some cases, full length proteins identified from the databasesdescribed herein are not particularly advantageous in view of one ormore selection requirements defined by one or more important parameters,or otherwise do not provide enough of one or more specific amino acid(s)by mass relative to the total mass of the nutritive polypeptide. Inthese cases, one or more fragments (also termed “regions” herein) ofnutritive polypeptides identified in the database are able meet thedesired search criteria. Databases containing possible fragments ofnutritive polypeptides are generated and searched by taking each fulllength sequences in the database and examining all possible subsequencesat least 25 amino acids in length contained therein. For example, it wasdesired to find a nutritive polypeptide sequence that had leucine massfractions greater than about 0.2 and highly charged to increase thelikelihood of soluble expression. The protein edible species databasedescribed herein was searched using a solvation score cutoff of lessthan −30, and in order to reduce the likelihood that these proteinswould elicit an allergenic response, upper bounds of 50% were set forthe global allergen homology and allergenicity scores. In order toreduce the likelihood that these proteins would have toxic effects uponingestion, an upper bound of 35% was set for the toxicity score. Inorder to reduce the likelihood that these proteins would act asinhibitors of digestive proteases, an upper bound of 35% was set for theanti-nutricity score.

An exemplary list of the top 10 nutritive polypeptide fragments that areenriched in leucine (≦20% by mass) and meet the afore mentioned cutoffsin solvation score, global allergen homology, allergenicity score,toxicity score, and anti-nutricity score is shown in table E9A.

TABLE E9A DBID EAA L P58797 0.47 0.26 A7A1V1 0.49 0.24 P04467 0.56 0.23Q9AWA5 0.45 0.22 Q2NL14 0.52 0.22 Q60CZ8 0.42 0.22 Q10MN8 0.32 0.22P50275 0.47 0.22 Q2YDE5 0.45 0.22 Q0P5B4 0.51 0.22

An exemplary list of the top 10 nutritive polypeptide fragments from theexpressed protein database that are enriched in leucine (120% by mass)is shown in Table E9B.

TABLE E9B SEQID EAA L SEQID-00132 0.60 0.32 SEQID-00195 0.52 0.26SEQID-00194 0.54 0.26 SEQID-00193 0.53 0.26 SEQID-00166 0.65 0.26SEQID-00134 0.58 0.24 SEQID-00212 0.51 0.23 SEQID-00139 0.49 0.23SEQID-00213 0.51 0.21 SEQID-00148 0.47 0.21

Example 10 Purification of Nutritive Polypeptides

Various methods of purification have been used to isolate nutritivepolypeptides from or away other materials such as raw foods, cells,salts, small molecules, host cell proteins, and lipids. These methodsinclude diafiltration, precipitation, flocculation, aqueous two phaseextraction, and chromatography.

Purification by Anti-FLAG Affinity Chromatography.

Anti-FLAG purification provides a method to purify nutritivepolypeptides from low-titer expression systems or from similarly chargedhost cell proteins. Nutritive polypeptides were engineered to containeither a single FLAG tag (DYKDDDDK) or a triple tandem FLAG tag(DYKDDDDKDYKDDDDKDYKDDDDK) appended to the C-terminus of the protein.Anti-FLAG affinity purification offers a single-step purificationprocess that offers non-denaturing process conditions and elutionpurities of >95% (Einhauer et al., 2001 Journal of Biochemical andBiophysical Methods).

Nutritive polypeptides were purified using Anti-FLAG M2 Affinity AgaroseGel (Sigma Aldrich, St. Louis, Mo.). The M2 affinity resin is designedspecifically for use with C-terminal FLAG epitopes. For purification ofN-terminally appended FLAG epitopes, the M1 Affinity Agarose Gel wasused. The M2 Affinity Agarose Gel (resin) has an advertised staticbinding capacity (SBC) of approximately 0.5 mg nutritive polypeptide permL of resin.

Purification of nutritive polypeptides from Aspergillus niger secretionmedia and Bacillus subtilis secretion media were performed using 20-40mL of anti-FLAG resin. Prior to purification, secretion media wasadjusted to 150 mM NaCl and pH 7.4. Resin was equilibrated by rinsingthe media with an excess of 1× tris-buffered saline (TBS) pH 7.4 t 0.1and collecting it through a 0.2 um polyethersulfone (PES) vacuum filter.Equilibrated resin was then mixed with secretion media in batch mode andallowed to mix at room temperature for one hour. Unbound material wasremoved from the resin by passing the entire mixture through a 0.2 umPES vacuum filter. The resin was physically collected on the surface ofthe filter and was subsequently washed with 20 resin volumes of TBS pH7.4±0.1 to further remove unbound material through the 0.2 um PES vacuumfilter. Washed resin was transferred to drip columns (10 mL each) andthe bound polypeptides were eluted with two column volumes (CV) of 0.1Mglycine pH 3.0. The eluted polypeptides were flowed directly from thedrip columns into conical tubes that contained 1M Tris pH 8.0; thisstrategy was used to neutralize the pH of the eluted polypeptidesolution as quickly as possible. Resin was regenerated using anadditional 3 CV of 0.1M glycine pH 3.0. For short term storage, resinwas stored in 1×TBS pH 7.4 at 4° C.: for long term storage, resin wasstored in 0.5×TBS pH 7.4, 50% glycerol at −20° C.

Exemplary anti-FLAG purification of SEQID-00105 from B. subtilis yielded4.0 mg of protein in a 4.3 ml elution. The sample was loaded onto apolyacrylamide gel at three different dilutions for increasedsensitivity and SEQID-00105 was found to be 95% pure. Exemplaryanti-FLAG purification of SEQID-00298 from A. niger was performedaccording to the same procedure. The elution fraction was neutralized,as described, and analyzed by SDS-PAGE and Bradford assay as describedherein. The main band in the elution was found to be 95% pure. The mainband in the elution is compared to the MW ladder on the same gel, andmatched the expected molecular weight of SEQID-00298. Forty mL ofanti-FLAG resin captured 4.0 mg of material, resulting in an estimatedresin capacity of 0, 10 mg/mL.

Purification by 5 ml Immobilized Metal Affinity Chromatography (IMAC).

E. coli was grown in shake flask fermentation with targeted expressionof individual nutritive polypeptides with HIS8 tags, as describedherein. Cells were harvested from each shake-flask by bucketcentrifugation. The supernatant was discarded, and the cells weresuspended in 30 mM imidazole, 50 mM sodium phosphate, 0.5 M NaCl, pH 7.5at a wet cell weight (WCW) concentration of 20% w/v. The suspended cellswere then lysed with two passes through a M110-P microfluidizer(Microfluidics, Westwood, Mass.) at 20,000 psi through an 87 uminteraction chamber. The lysed cells were centrifuged at 15,000 relativecentrifugal force (RCF) for 120 minutes, and then decanted. Cellulardebris was discarded, and the supernatants were 0.2 um filtered. Thesefiltered protein solutions were then purified by immobilized metalaffinity chromatography (IMAC) on an AKTA Explorer 100 FPLC (GEHealthcare, Piscataway, N.J.). Nutritive polypeptides were purified over5 mL (1.6 cm diameter×2.5 cm height) IMAC Sepharose 6 Fast Flow columns(GE Healthcare, Piscataway, N.J.).

IMAC resin (GE Healthcare, IMAC Sepharose 6 Fast Flow) was charged withnickel using 0.2 NiSO4 and washed with 500 mM NaCl, 200 mM imidazole, pH7.5 followed by equilibration in 30 mM imidazole, 50 mM sodiumphosphate, 0.5 M NaCl, pH 7.5, 50 mL of each protein load solution wasapplied onto a 5 mL IMAC column, and washed with additionalequilibration solution to remove unbound impurities. The protein ofinterest was then eluted with 15 mL of IMAC Elution Solution, 0.25 Mimidazole, 0.5 M NaCl, pH 7.5. All column blocks were performed at alinear flow rate of 150 cm/hr. Each IMAC elution fraction was bufferexchanged by dialysis into a neutral pH formulation solution. Thepurified proteins were analyzed for concentration and purity bycapillary electrophoresis and/or SDS-PAGE. Concentration was also testedby Bradford and A280 measurement, as described herein. Table E9Ademonstrates a list of nutritive polypeptides that were purified by IMACat 5 mL scale.

TABLE E9A Nutritive polypeptides that were purified by IMAC at 5 mLSEQID Mass (mg) Purity 00533 3  22% 00522 25.5  36% 00085 34  51% 001034.5  56% 00359 40.5  56% 00346 30.7  56% 00510 112  61% 00622 70  70%00522 47  72% 00546 235.6  75% 00353 5.6  76% 00601 83.8  77% 00418 14 80% 00502 93.2  84% 00100 68  87% 00606 77.8  87% 00104 93  89% 0007692  91% 00341 176.6  91% 00598 60.3  91% 00647 73.7  93% 00105 3.8  93%00343 35.3  95% 00103 112  95% 00511 179  95% 00354 85.8  96% 00587 93 96% 00610 90.5  97% 00485 269  98% 00356 76.9  98% 00352 134.9  99%00345 196.2 100% 00338 123.2 100% 00298 0.6 100% 00357 104.8 100% 00605202 100% 00559 241.8 100% 00338 268 100%

Purification by IL Immobilized Metal Affinity Chromatography (IMAC).

E. coli was grown in 20 L fermentation with targeted expression ofindividual nutritive polypeptides with HIS8 tags, as described herein.Cells were harvested from the fermenter and centrifuged using a SharplesAS-16P centrifuge to collect wet cell mass. Cells were subsequentlyresuspended in 30 mM imidazole, 50 mM sodium phosphate, 0.5 M NaCl, pH7.5 at a wet cell weight (WCW) concentration of 20% w/v. The cellsuspension was then lysed using four passes through a Niro SoaviHomogenizer (Niro Soavi, Parma, Italy) at an operational pressure of12,500-15,000 psi and a flow rate of 1 L/min. The lysate was clarifiedusing a Beckman J2-HC bucket centrifuge (Beckman-Coulter, Brea, Calif.)at 13,700×g for 1 hour. Cellular debris was discarded, and thesupernatant was filtered through a Sartopore 11 XLG 0.8/0.2 um filter(Sartorius Stedim, Bohemia. N.Y.) at 30 L/m2/hr. Filtered lysate waspurified by IMAC using IMAC Sepharose 6 Fast Flow resin packed in a 0.9L column (9 cm diameter×13.8 cm height).

IMAC resin was equilibrated, as described herein, at a linear flow rateof 300 cm/hr. Once equilibrated, the entirety of the filtered lysate waspassed over the column at a linear flow rate of 150 cm/hr. Load volumesranged from six to ten column volumes. After the load, unbound materialwas washed off of the column, and the target protein was eluted. Elutionpools were shipped at room temperature, 4° C. or frozen. This decisionwas dependent on the stability of the nutritive polypeptide in ElutionSolution. Table E9B summarizes a number of nutritive polypeptides thathave been purified by IMAC at the 1 L column scale.

TABLE E9B Nutritive polypeptides that have been purified by IMAC at 1 Lscale SEQID IMAC Elution Mass IMAC Elution Purity 00240 9.00 grams  98%00338 43.5 grams 100% 00341 54.3 grams 100% 00352 19.8 grams 100% 0055919.5 grams  89% 00587  8.6 grams  69%

Nutritive polypeptides were filtered through a Sartopore II XLG 0.8/0.2□□ m filter and loaded directly into an ultrafiltration/diafiltration(UF/DF) unit operation. Membrane area and nominal molecular weightcutoff were chosen as appropriate for each nutritive polypeptide.Nutritive polypeptides were ultrafiltered at a cross flow of 12 L/m2/minand a TMP target of 25 psi. Nutritive polypeptides were concentratedapproximately ten-fold on Hydrosart ultrafiltration cassettes (SartoriusStedim, Bohemia, N.Y.), and diafiltered seven diavolumes into aformulation buffer that is specific to the nutritive polypeptide.Ultrafiltration permeate was discarded. The diafiltered, concentratedretentate was collected, filtered through a 0.22 um membrane filter andfrozen at −80° C.

In some cases, frozen protein concentrates were lyophilized using aLabconco lyophilizer (Labconco, Kansas City, Mo.). Residual watercontent of the cake is analyzed using the Karl Fisher method.

Purification by 10 L Immobilized Metal Affinity Chromatography (IMAC).

E. coli was grown in 250 L fermentation with targeted expression ofindividual nutritive polypeptides with HIS8 tags, as described herein.Cells were harvested from the 250 L fermenter and centrifuged using aSharples AS-16P centrifuge to collect wet cell mass. Cells weresubsequently resuspended in 30 mM imidazole, 50 mM sodium phosphate, 0.5M NaCl, pH 7.5 at a WCW concentration of 20% w/v. The cells suspensionwas then lysed using four passes through a Niro Soavi Homogenizer (NiroSoavi, Parma, Italy) at an operational pressure of 12,500-15,000 psi anda flow rate of 1 L/min. Clarified lysate was generated using four passesthrough a Sharples AS-16P centrifuge at 15,000 rpm operated at 0.5L/min. Cellular debris was discarded, and the supernatant was filteredthrough a series of filters. Clarified lysate was passed sequentiallythrough a SartoPure GF+0.65 um, a SartoGuard PES 1.2/0.2 um and aSartopore II XLG 0.8/0.2 um filter (Sartorius Stedim, Bohemia, N.Y.).Filtered lysate was purified by IMAC using IMAC Sepharose 6 Fast Flowresin packed in an 8.5 column (20 cm diameter×27.1 cm height).

IMAC resin was equilibrated as described at a linear flow rate of 150cm/hr. Once equilibrated, the filtered lysate was passed over the columnat a linear flow rate of 150 cm/hr. Load volumes ranged from 3.8 to 5.0CV. After the load, unbound material was washed off of the column withadditional equilibration. Nutritive polypeptides manufactured at the 10L IMAC scale were subject to an additional set of washes with 2 CV of 10mM sodium phosphate dibasic, 300 mM NaCl 3 CV of 0.5% w/v sodiumdeoxycholate, 50 mM sodium phosphate dibasic, 300 mM NaCl: and 5CV of 10mM sodium phosphate dibasic, 300 mM NaCl. Following the washes, thetarget polypeptide was eluted as described. Elution pools were stored atroom temperature.

Multiple nutritive polypeptides were purified by IMAC chromatography atthe 10 L column scale. Table E9C summarizes the purification ofSEQID-00105 and SEQID-00338. FIG. 1 provides an exemplary SDS-PAGEanalysis of the purification of SEQID-00105.

TABLE E9C Nutritive polypeptides were purified by IMAC chromatography atthe 10 L column scale SEQID Mass Purity 00105 179 g  98% 00105 265 g 98% 00105 131 g  91% 00105 147 g  92% 00105 164 g  94% 00105 148 g  95%00105 229 g 100% 00105 228 g 100% 00338 137 g  92% 00338 196 g 100%00338 169 g 100%

After IMAC purification at the 10 L column scale, nutritive polypeptideswere filtered through a Sartopore II XLG 0.8/0.2 um filter and loadeddirectly into an ultrafiltration/diafiltration (UF/DF) unit operation.Membrane area and nominal molecular weight cutoff were chosen asappropriate for each nutritive polypeptide. Nutritive polypeptides wereultrafiltered at a cross flow of 12 L/m2/min and a TMP target of 25 psi.Nutritive polypeptides were concentrated approximately ten-fold onHydrosart ultrafiltration cassettes (Sartorius Stedim, Bohemia, N.Y.),and diafiltered sequentially into four diavolumes of 10% phosphatebuffered saline (PBS), pH 8.7; followed by two diavolumes of 25 mMtetrasodium ethylenediaminetetraacetic acid (Na4EDTA); followed by sevendiavolumes of 10% PBS, pH 8.7. Intermediate diafiltration into Na4EDTAwas performed in order to chelate any leached nickel(II) from the IMACresin. Ultrafiltration permeate was discarded; the diafiltered,concentrated retentate was filtered through a 0.2 um membrane filter,and frozen at −80° C.

The ultrafiltration pool was filtered with a sterilizing-grade filterwith the goal of bioburden reduction. The nutritive polypeptide wasfiltered into glass trays that were rinsed with ethanol. Filled glasstrays were subsequently frozen at −80° C. The frozen material was thenlyophilized to a dry cake using a Labconco lyophilization unit(Labconco, Kansas City, Mo.). The mass of the protein in the tray wasmonitored with time, until it plateaued, which was considered to becomplete drying. The dried protein cake was sealed by the lid of thetray, and over-packaged by vacuum sealing in a plastic bag. The entirepackage was stored at −80° C.

Ion Exchange Chromatography.

Selecting an appropriate method of purifying a nutritive polypeptide hasimplications for the speed of process development, cost of manufacture,final purity, and robustness of the purification. Nutritive polypeptideshave been isolated by various chromatographic methods. The mode ofchromatography selected for use depends on the physicochemicalproperties of the target nutritive polypeptide.

Charged nutritive polypeptides bind to ion exchange chromatography resinthrough electrostatic interactions.

In the present application, we have defined two methods of screening alibrary of polypeptides to rank-order them for their ability to bind toion exchange resins. One method is an in silico prediction based oncalculation of protein net charge across a range of pH using the primarysequence of the polypeptides, as described herein. The second method isa multiplexed purification screen in vitro, as described herein. The twomethods have successfully been used independently of each other, andthey have been used together on the same set of 168 nutritivepolypeptides with supportive data, as described herein.

The in silico method of predictive ranking for ion exchange purificationis based on calculating net charge of a nutritive polypeptide at a rangeof pH based on the primary sequence. The primary sequence of a nutritivepolypeptide is used to predict the mode of chromatography that is mostlikely to successfully isolate that nutritive polypeptide from host cellproteins and other impurities. Highly charged nutritive polypeptides arelikely to bind tightly to ion exchange chromatography resin. Thetightest binding is achieved for nutritive polypeptides which have onepredominant charge, either positive or negative. It is possible for anutritive polypeptide with a mixture of positive and negative charges tohave tight binding to ion exchange resin, but it is also possible thatthose charges may work against each other. Similarly, a nutritivepolypeptide with alternating positive and negative patches on itssurface may not bind as tightly as one with a dominant portion of itssurface that is one single charge. Similarly, a nutritive polypeptidethat has a strongly positive or negative terminus, tail, tag, or linkersequence may effectively display that highly charged group allowing forextremely tight binding.

A prevalence of one or more certain amino acids, e.g., histidine,arginine, and lysine in a polypeptide imparts in that polypeptide, or aportion thereof, a positive charge when the pH of the protein solvent isbelow the pKa of the one or more amino acids. Polypeptide chargeincludes total protein charge, net charge, or the charge of a portion ofthe polypeptide. In embodiments wherein a polypeptide or portion thereofis positively charged, a cation exchange resin is used.

A prevalence of one or more certain amino acids, e.g., glutamic acid andaspartic acid in a polypeptide imparts in that polypeptide, or a portionthereof, a negative charge when the pH of the protein solvent is abovethe pKa of the one or more amino acids. Polypeptide charge includestotal protein charge, net charge, or the charge of a portion of thepolypeptide. In embodiments wherein a polypeptide or portion thereof isnegatively charged, an anion exchange resin is used.

The net charge of a polypeptide changes as a function of the pH of theprotein solvent. The number of positive charges and negative charges canbe calculated at any pH based on the primary sequence of thepolypeptide. The sum of the positive charges and negative charges at anyone pH results in the calculated net charge. The isoelectric point (pI)of the polypeptide is the pH at which its calculated net charge is 0. Tomake comparisons, the net charge of a sequence is normalized by thenumber of amino acids in the sequence and the parameter “net charge peramino acid” results as the novel comparator between sequences, which isused to predict chromatographic performance.

Nutritive polypeptide sequences have been evaluated by calculating thenet charge per amino acid of each polypeptide at every pH (1-14).Additionally, the pI of each polypeptide was calculated. Nutritivepolypeptides were ranked by pI and by net charge per amino acid.Polypeptides with a low pI and very negative net charge per amino acidacross a wide range of pH are predicted to bind to anion exchangechromatography resin with high affinity. Polypeptides with a high pI andvery positive net charge per amino acid across a wide range of pH arepredicted to bind to cation exchange chromatography resin with highaffinity. In some embodiments herein, only a portion of the polypeptideis charged (as in a terminus, tail, tag, or linker), it is recognizedthat the pI and net polypeptide charge may be variable, and otherfactors or empirical measurements may be useful to predict the bindingaffinity of such a polypeptide to chromatography resins.

FIG. 2 demonstrates example nutritive polypeptides, which, based onprimary sequence, are predicted to bind to either anion or cationexchange resin. Nutritive polypeptides with a pI of <4.0, and a netcharge per amino acid that is negative across a broad range of pH arepredicted to bind anion exchange resin with high affinity ((1)SEQID-00105, (2) SEQID-00008, (3) SEQID-00009, (4) SEQID-00475).Nutritive polypeptides with a pI of >10.0, and a net charge per aminoacid that is positive across a broad range of pH are predicted to bindcation exchange resin with high affinity ((5) SEQID-00472, (6)SEQID-00640, (7) SEQID-0019).

The primary sequence analyses presented herein indicate that SEQID-00105and SEQID-00009 are likely to bind to anion exchange chromatographyresin with high affinity, and that SEQID-00640 is likely to bind tocation exchange chromatography resin with high affinity. Thesepredictions were tested and demonstrated to be true, as demonstrated inthe following four examples of polypeptide purification after microbialcell culture. In the first example, SEQID-00(09 was purified directlyfrom lysed E. coli cells to 99% purity using anion exchangechromatography. In the second example, SEQID-00105 was isolated frombacillus subtilis supernatant by anion exchange chromatography. In thethird example, SEQID-00105 expressed intracellularly in E. coli wasrefined to 100% purity using anion exchange chromatography after it hadbeen initially purified by IMAC chromatography. In the fourth example,SEQID-00640 was isolated from bacillus subtilis supernatant by cationexchange chromatography.

SEQID-00009 was expressed intracellularly in E. coli, as describedherein. The cells were suspended in solution and ruptured. Threesolutions were tested (0.1 M Na2CO3 pH 11.4, 0.1 M tris HCl pH 4.1, and0.1 M potassium phosphate pH 7.0). These lysed solutions were clarifiedby centrifugation and mixed with anion exchange resin for binding. Tworesins were tested (Fractogel® EMD TMAE Hicap (M) from EMD and POROS® D50 μm from Life Technologies). These six binding conditions wereperformed in batch mode and the resins were washed with the appropriatelysis buffer to remove any unbound protein. The maximally-bound dampresin was then transferred to smaller drip columns. Each drip column wasthen eluted with up to six sequential washes of increasing NaClconcentration (each NaCl wash solution was buffered with the appropriatelysis buffer). SEQID-00009 was eluted in these fractions, collected, andanalyzed by chip electrophoresis, as described herein. SEQID-00009 wasidentified as an eluting band at the expected molecular weight. In everycase, SEQID-00009 eluted from the drip column at a purity higher thanthe load purity. This observation indicates that SEQID-00009 did bind tothe anion exchange resins, as predicted, and that purification wasachieved. The maximum purity achieved was 99%. In every case,SEQID-00009 was among the last proteins to elute from the resinindicating that the binding affinity of SEQID-00009 to two resins at arange of pH is generally higher than the binding affinity of any hostcell protein from E. coli.

Microbial cell culture of Bacillus subtilis was performed as describedherein expressing and secreting SEQID-00105 into the fermentation media.The cells were removed by centrifugation, and the supernatant wasfurther clarified by membrane filtration. The clarified supernatant wasconcentrated by ultrafiltration to decrease load time on the anionexchange column and the solution was exchanged into a low salt solutionbuffered at pH 6.0. This solution was passed over a chromatographycolumn (1 cm diameter, 20 cm height) containing POROS® XQ Strong AnionExchange Resin from Life Technologies. The unbound proteins were rinsedfrom the resin with 20 mM Bistris, pH 6.3. The bound proteins were theneluted using a 30 column volume gradient to 400 mM NaCl, 20 mM Bistris,pH 6.3. The column effluent was collected in sequential fractions andanalyzed by chip electrophoresis, as described herein. SEQID-00105 wasidentified as an eluting band at the expected molecular weight. Themaximum purity achieved in one fraction was 100%.

SEQID-00105 was expressed intracellularly in E. coli, as describedherein. The cells were ruptured, and the SEQID-00105 was purified byIMAC chromatography, according to the procedure described herein. TheIMAC elution pool was further refined to 100% purity using anionexchange chromatography. The IMAC elution pool was concentrated and thendiluted into 50 mM tris pH 8.0. This solution was then passed through acolumn (1.6 cm diameter, 20 cm height) packed with anion exchange resin:Fractogel® EMD TMAE Hicap (M) from EMD. The bound protein was rinsedwith equilibration solution, and then eluted with 350 mM NaCl 50 mM trispH 8.0. This procedure was repeated multiple times, and all samples wereanalyzed by chip electrophoresis, as described herein. The elutionsamples ranged from 79% to 99% pure.

Microbial cell culture of Bacillus subtilis was performed as describedherein expressing and secreting SEQID-00640 into the fermentation media.The cells were removed by centrifugation, and the supernatant wasfurther clarified by membrane filtration. The clarified supernatant wasdiluted 1:2 with deionized water and titrated to pH 5 with 1 M aceticacid. The resulting solution was membrane filtered prior to loading ontoa cation exchange column (1.2 cm diameter 10 cm height) packed withPOROS® XS Strong Cation Exchange Resin from Life Technologies. The boundresin was flushed with a 50 mM Acetate, 50 mM NaCL pH 5.0 solution. Theprotein was then eluted with a 20 CV gradient to 1.05 M NaCl pH 5.0.Elution fractions were collected and analyzed by SDS-PAGE. CoomassieBlue Stain. The peak sample demonstrated 100% purity and no impuritieseluted later in the gradient, indicating that the SEQID-00640polypeptide bound to the cation exchange resin with more affinity thanany host cell proteins.

Purification by Precipitation.

Protein Precipitation is a Well-Known Method for purification ofpolypeptides (Scopes R. 1987. Protein Purification: Principles andPractice, New York: Springer). Many polypeptides precipitate as saltconcentrations increase, a phenomenon known as salting out. Salt typeshave been ranked and organized on the Hofmeister series for theirdifferent abilities to salt out proteins (F. Hofmeister Arch. Exp.Pathol. Pharmacol. 24, (1888) 247-260.). Proteins also have differentpropensity to precipitate due to high salt concentration based on theirphysicochemical properties, however, a universal metric to rank proteinsfor this characteristic has not been established. The use of such aranking metric to select nutritive polypeptides for their ability to bepurified has implications for the speed of process development, cost ofmanufacture, final purity, and robustness of the purification.

In most industrial applications of purification by polypeptidesprecipitation, the polypeptide of interest is selectively precipitated,and the impurities are then rinsed away from the solid precipitate. Incertain embodiments, polypeptides do not precipitate with high levels ofsalt, and purification is achieved by precipitating the impurities. Inthe present application, we have defined two methods of screening alibrary of polypeptides to rank-order them for their ability to remainsoluble through harsh precipitation conditions. One method is an insilico prediction based on calculation of protein total charge across arange of pH using the primary sequence of the polypeptides, as describedherein. The second method is a multiplexed purification screen in vitro,as described herein. The two methods have successfully been usedindependently of each other, and they have been used together on thesame set of 168 nutritive polypeptides with supportive data, asdescribed herein.

The solubility of a polypeptide correlates directly with the abundanceof surface charges (Jim Kling, Highly Concentrated Protein Formulations:Finding Solutions for the Next Generation of Parenteral Biologics,BioProcess International, 2014.). It has been established that surfacecharges can impart physical characteristics to a polypeptide (Lawrence.M. S., Phillips, K. J., & Liu, D. R. (2007). Supercharging proteins canimpart unusual resilience. Journal of the American Chemical Society,129(33), 10110-2, doi:10.1021/ja071641y).

The in silico method of predictive solubility ranking is based oncalculating total number of charges of a nutritive polypeptide at arange of pH based on the primary sequence.

A prevalence of one or more certain amino acids, e.g., histidine,arginine, and lysine in a polypeptide imparts in that polypeptide, or aportion thereof, a positive charge when the pH of the protein solvent isbelow the pKa of the one or more amino acids. A prevalence of one ormore certain amino acids, e.g., glutamic acid and aspartic acid in apolypeptide imparts in that polypeptide, or a portion thereof, anegative charge when the pH of the protein solvent is above the pKa ofthe one or more amino acids.

The total number of charges of a polypeptide changes as a function ofthe pH of the protein solvent. The number of positive charges andnegative charges can be calculated at any pH based on the primarysequence of the polypeptide, as described herein. The sum of thepositive charges and negative charges at any one pH results in thecalculated net charge. The isoelectric point (pI) of the polypeptide isthe pH at which its calculated net charge is 0. To make comparisonsacross nutritive polypeptides, the total number of positive charges isadded to the total number of negative charges (the absolute value), andthat total charge is normalized by the number of amino acids in thesequence, and the parameter “total charge per amino acid” results as thenovel comparator between sequences, which is used to predict thepolypeptide's resistance to precipitation. The more resistant apolypeptide is, the higher the likelihood that it can be purified to ahigh degree by precipitating out the impurities. Unlike predictingchromatographic performance, solubility is not affected by the polarityof the charges. While it is often true that a polypeptide experiencesits lowest solubility at the pI of the sequence, some polypeptides havea high total charge and are still extremely soluble at their pI, asshown herein.

Nutritive polypeptide sequences have been evaluated by calculating thetotal charge per amino acid of each polypeptide at a range of pH (1-14).Nutritive polypeptides were ranked by total charge per amino acid.Polypeptides with a low pI and very negative net charge per amino acidacross a wide range of pH and polypeptides with a high pI and verypositive net charge per amino acid across a wide range of pH are allexpected to score equally well by this ranking. Polypeptides with alarge number of both charges score the best.

FIG. 3 demonstrates example nutritive polypeptides, which, based onprimary sequence, are predicted to have extremely high solubility. Thisset includes polypeptides with a low pI (<4) and very negative netcharge per amino acid across a wide range ((1) SEQID-00475. (2)SEQID-00009). This set includes polypeptides with a high pI (>10) andvery positive net charge per amino acid across a wide range of pH ((4)SEQID-00433, (5) SEQID-00472). This set includes polypeptides with moreneutral pI ((3) SEQID-00478). Many of the polypeptides displayed hereshow high charge even at extreme pH values, such as <4 and >12. Theentire set is expected to be extremely soluble and resist precipitationacross a wide range of pH.

In this demonstration, the E. coli cells were harvested from shake flaskfermentation by centrifugation, and the whole cells were distributedinto tubes (1 gram of cells per tube). To each tube, 4 mL of lysissolution was added, and cells were lysed by sonication at 75 Amps for 30seconds. Lysis solutions included: Water, 8 M Urea 0.1 M Tris 0.1M NaCl,0.1 M Acetate 10% gly 0.1% Tween-80 0.3 M Arg 0.3M NaCl 10 mM EDTA, 10mM Imidazole pH 5.0, 0.1 M Acetate 10% gly 0.1% Tween-80 0.3 M Arg 0.3MNaC 10 mM EDTA, 10 mM Imidazole pH 7.0, 100 NaCl 100 Hepes 10 ImidazolepH 7.5, 500 NaCl 100 Hepes 10 Imidazole pH 7.5, 100 mM Phos, 150 mMNaCl, 10 mM Imidazole pH 7.5, 0.1 M NaCl 0.1 M Hepes 10 mM Imidazole 50mM CaCl2 PH 7.5, 0.1 M Hepes 3.5 M Am Sulfate pH 7.5, 0.1 M Hepes 2 MAm. Sulfate pH 7.5, 0.1 M Tris, 0.1 M Tris 0.5 M NaC, 150 mM NaCl 10 mMAcetate 15 mM Imidazole pH 6.04, and 500 mM NaCl 100 mM Acetate 15 mMImidazole pH 6.04. The lysate was clarified by centrifugation and 0.2 umfiltration. The clarified supernatant was analyzed by SDS-PAGE (bluestain), as described herein. SEQID-00009 demonstrated solubility in eachof these conditions. E. coli host cell proteins generally demonstratedsolubility in these conditions as well, with one exception. In thepresence of 3.5 M ammonium sulfate effectively precipitated the majorityof the host cell proteins resulting in 85% purified SEQID-00009 afterthe cell harvest stage of the process. This result indicates thatSEQID-00009 is more soluble than most E. coli host cell proteins andthat precipitation can be used as part of a low cost method forisolation. This correlates with the high total charge of SEQID-00009 andsupports that the prediction is accurate. Furthermore, it is predictedthat polypeptides with more charge than SEQID-00009 would be even moresoluble which could have the benefit over SEQID-00009 of higherpolypeptide yield.

In subsequent experiments, SEQID-00009 was purified to 99% purity with asingle stage of ammonium sulfate precipitation. In this demonstration,the E. coli cells were harvested from shake flask fermentation bycentrifugation, and the whole cells were suspended in 0.1 M sodiumcarbonate, pH 10 (1 gram of cells in 4 mL of solution). The cells werelysed by sonication (80 Amp for 2 minutes). The lysate was clarified bycentrifugation and 0.2 Um membrane filtration. The clarified supernatantwas divided into a series of 3 mL fractions, to which a stock solutionof 4 M ammonium sulfate, pH 9.8 was added. Variable amounts of stocksolution were added to achieve a range of ammonium sulfateconcentrations. The samples were mixed for 10 minutes at roomtemperature, and clarified by centrifugation and 0.2 um membranefiltration. The clarified supernatants were analyzed by SDS-PAGE (bluestain), as described herein. FIG. 4 shows the purity of SEQID-00009 isas a function of ammonium sulfate concentration.

Multiplexed Purification: Ion Exchange Chromatography. In some cases, anentire library of proteins is tested in a multiplexed screeningexperimental platform, 168 nutritive polypeptides were transfected andexpressed in a multiplexed expression system in which a single growthcondition was used to produce each polypeptide in a single container.This multiplexed expression system allows any set of polypeptidesequences to be tested in parallel for a wide range of manufacturabilityparameters, each of which can be used to rank order the set ofpolypeptides being examined. A set of manufacturability parametersincludes expression level, polypeptide solubility, ability ofpolypeptide to be purified by chromatography, ability to resist thermaldenaturation, ability of polypeptide to digest, ability of polypeptideto be purified by resisting harsh treatments.

The set of 168 nutritive polypeptides was tested for intracellularexpression in E. coli. The solubly expressed polypeptides werepre-treated as a group and then subjected to a series of purificationconditions so that the set could be rank ordered in terms of their easeof purification by multiple methodologies. As described herein, it isexpected that the same subset of proteins will be identified from eachexpression system to bind a particular mode of chromatography based onthe primary sequence analysis, specifically net charge per amino acid.

For E. coli multiplexed purification, the set of nutritive polypeptidesequences was HIS8 tagged. The cells were cultured, as described herein,ruptured, and the solution was clarified, as described herein. Thisproduction resulted in a solution containing all of the polypeptidesfrom the set which were both expressed and soluble. That set of solublepolypeptides was passed over an 5 ml IMAC column, and eluted, asdescribed herein. This IMAC purification effectively isolated thesolubly expressed nutritive polypeptides as a set by removing themajority of E. coli host cell proteins. The elution fraction wasconcentrated and buffer exchanged into a low salt solution buffered nearneutral pH before testing various purification methods. The methodstested include anion exchange chromatography, cation exchangechromatography, and negative precipitation, in which the impuritiesprecipitate and the polypeptides that remain soluble rank the highest.In this case, impurities have been removed, so the polypeptides are rankordered amongst themselves. Additionally, the set of proteins was testedfor thermal stability, by heating, wherein the polypeptides which remainsoluble after heating are more thermal stable than those whichprecipitate.

This mixture of polypeptides was rank ordered for their ability to bindanion exchange and cation exchange chromatography resins. Fourchromatography resins were tested. Two anion exchange resins: CaptoDEAE, from GE Lifesciences and Eshmuno®, Q Resin from EMD. Two cationexchange resins: POROS®, XS Strong Cation Exchange Resin from LifeTechnologies and Eshmuno® S Resin from EMD. Each resin was tested witheight different buffering conditions, as follows. Buffers used for anionexchange: Water (no buffer), pH 7; 15 mM Na2HPO4, pH 8.7; 30 mM Na2HPO4,pH 9.0; 15 mM Tris Base, pH 9.6; 30 mM Tris Base, pH 10.0; 30 mM Na2CO3,pH 11.2; 25 mM Arginine, pH 10.1. Buffers used for cation exchange:Water(no buffer), pH 7; 15 mM KH2PO4, pH 4.2; 30 mM KH2PO4, pH 4.5; 15 mMTris Acid, pH 4.9; 30 mM Tris Acid, pH 4.7; 15 mM MES Acid, pH 3.9; 25mM MES Acid, pH 4.1.

The resins were distributed to a 96 well filterplate (20 uL of resin perwell) and each was equilibrated three times. The protein set was mixedwith the equilibration buffers and allowed to bind to the resins. Theunbound proteins in solution were separated from the resin bycentrifuging the liquid through the filterplate for collection in a 96well plate below. The remaining unbound proteins were further rinsed offthe resin with a wash of equilibration buffer. The bound proteins werethen sequentially eluted with three stages of increasing saltconcentration (50, 250, 1500 mM NaCl buffered in the appropriate set ofbuffers above). The loosely bound proteins were removed first, and theproteins that were removed in the final elution condition were verytightly bound to the resin. Thus, a library of 168 proteins wasexpressed in E. coli and rank ordered for their binding affinity toanion exchange and cation exchange chromatography resin.

The experiment described herein produced 160 samples (four resins, eightbuffers, five collections). The five collection stages include: the flowthrough fraction, the wash fraction, the 50 mM NaCl elution, the 250 mMNaCl elution, and the 1500 mM NaCl elution. All 160 samples wereanalyzed by UV-vis absorbance at 280 nm, by Bradford total proteinassay, by Chip electrophoresis, and select samples were analyzed byLC/MS/MS. All analytical assays are described herein.

The assays demonstrated that some protein flowed through the resin andwas not bound. In most cases, the wash fraction did not elute asignificant amount of protein, indicating that any further protein toelute was in fact bound to the resin. As the NaCl concentrationincreased, the total protein being removed also increased demonstratingsuccessful binding and elution in nearly every condition. The proteinsdetected by electrophoresis in 1500 mM NaCl elution conditions remainedbound through the 250 mM NaCl wash condition, indicating strong binding.Select conditions were selected for LC/MS/MS analysis. The LC/MS/MSanalysis was performed with the 1500 mM NaCl elution sample from anionexchange chromatography resin (Capto DEAE) in the 30 mM Tris Basebuffering condition. The LC/MS/MS results were searched against thesequences of all 168 nutritive polypeptides originally expressed in thelibrary. Eight unique polypeptides were identified as having highbinding affinity to this anion exchange resin in this condition areSEQID-00341, SEQID-00346, SEQID-00497, SEQID-00525, SEQID-00555,SEQID-00605, SEQID-00606, SEQID-00610. For each polypeptide sequence inthis set, the net charge per amino acid was calculated based on primarysequence across the range of pH tested. As described herein, it isexpected that polypeptides which bind tightly to anion exchange resinshave a net charge per amino acid below 0 across the pH range, and thisis demonstrated to be true, with a single exception. Any exception isexpected to be due to the fact that there is charge heterogeneity acrossthe length of the sequence, and as described, net charge per amino aciddoes not always capture that. This multiplexed screen identified a setof polypeptides from a larger library based on their affinity to bindanion exchange resin, and this result can be predicted based on theprimary sequence analysis, as described herein.

The LC/MS/MS analysis was performed with the 1500 mM NaCl elution samplefrom cation exchange chromatography resin (Poros XS) in the 15 mM TrisAcid buffering condition. The LC/MS/MS results were searched against thesequences of all 168 nutritive polypeptides originally expressed in thelibrary. Eight unique polypeptides were identified as having highbinding affinity to this cation exchange resin in this condition areSEQID-00302, SEQID-495, SEQID-00522, SEQID-00537, SEQID-00546,SEQID-00547, SEQID-00560, SEQID-00598. For each polypeptide sequence inthis set, the net charge per amino acid was calculated based on primarysequence across the range of pH tested. As described herein, it isexpected that polypeptides which bind tightly to cation exchange resinshave a net charge per amino acid above 0 across the pH range, and thisis demonstrated to be true, with minor exception. Any exception isexpected to be due to the fact that there is charge heterogeneity acrossthe length of the sequence, and as described, net charge per amino aciddoes not always capture that. This multiplexed screen identified a setof polypeptides from a larger library based on their affinity to bindcation exchange resin, and this result can be predicted based on theprimary sequence analysis, as described herein.

In the Bacillus subtilis example of multiplexed purification, the set ofpolypeptide sequences was expressed without any type of purificationtag. The cells were cultured in flasks, as described herein andexpressed and secreted the polypeptides into the growth media. The cellswere removed by centrifugation and the solution was further clarified bymembrane filtration, as described herein. This production processresulted in a solution containing all of the polypeptides from the setwhich were both expressed and solubly secreted. That set of solublepolypeptides was concentrated and buffer exchanged into a solution ofphosphate, pH 7.0 before testing various purification methods. Themethods tested include anion exchange chromatography, cation exchangechromatography, and negative precipitation, in which the impuritiesprecipitate and the polypeptides that remain soluble rank the highest.In these multiplexed purification studies, the polypeptides are purifiedaway from each other and from the host cell proteins in order to be rankordered amongst themselves.

This mixture of polypeptides was rank ordered for their ability to bindto anion exchange and cation exchange chromatography resins. Fourchromatography resins were tested. Two anion exchange resins: CaptoDEAE, from GE Lifesciences and Eshmuno® Q Resin from EMD. Two cationexchange resins: POROS® XS Strong Cation Exchange Resin from LifeTechnologies and Eshmuno® S Resin from EMD. Each resin was tested witheight different buffering conditions. Buffers used for Anion Exchange:18 mM BIS-TRIS, pH 6.5; 13 mM HEPES, pH 7.0; 18 mM HEPES, pH 7.5; 16 mMTRIS, pH 8.0; 32 mM TRIS, pH 8.5; 88 mM TRIS, pH 9.0; 13 mM Na2CO3, pH9.5; 20 mM Na2CO3, pH 10.0. Buffers used for Cation Exchange: 19 mMCitrate, pH 3.0; 13 mM Citrate, pH 3.5; 49 mM Acetate, pH 4.0; 22 mMAcetate, pH 4.5; 14 mM Acetate, pH 5.0; 10 mM Acetate, pH 5.5; 24 mMMES, pH 6.0; 15 mM MES, pH 6.5.

The resins were distributed to a 96 well filterplate (50 μL of resin perwell) and each was equilibrated three times. The protein set was mixedwith the equilibration buffers and allowed to bind to the resins. Theunbound proteins in solution were separated from the resin bycentrifuging the liquid through the filterplate for collection in a 96well plate below. The remaining unbound proteins were further rinsed offthe resin with two wash cycles of equilibration buffer. The boundproteins were then sequentially eluted with increasing saltconcentration (250, 500, 1000 mM, 2000 mM NaCl). Each salt solution wasbuffered in the appropriate equilibration buffer except for the 2000 mMNaCl solution which was buffered with MES at pH 6.0 for anion exchangeresins and with TRIS at pH 8.0 for cation exchange resins. The looselybound proteins were removed first, and the proteins that were removed inthe final elution condition were very tightly bound to the resin. Thus,the library of proteins was expressed in Bacillus subtilis and rankordered for their binding affinity to anion exchange and cation exchangechromatography resin.

The experiment described herein produced 192 samples (four resins, eightbuffers, six collections). The six collection stages include: the flowthrough fraction, the wash fraction, the 250 mM NaC elution, the 500 mMNaCl elution, the 1000 mM NaCl elution, and the 2000 mM NaCl elution.All 192 samples were analyzed by Chip electrophoresis. Select sampleswere analyzed by SDS-PAGE. Select samples were analyzed by LC/MS/MS. Allanalytical assays are described herein. Identification of strongly boundproteins is performed by a combination of Chip electrophoresis,SDS-PAGE, and LC/MS/MS.

SDS-PAGE results demonstrate that the majority of polypeptides do notbind to these resins, in fact they are found in the flow throughfraction. Therefore, the polypeptides that bind to the resins are uniquein their ability to be purified from the majority of other polypeptides.The set of polypeptides in the various elution fractions have beenisolated from a larger set based on their properties in a purificationprocess, which has implications for the manufacture, cost, developmenttime, and eventual purity of these polypeptides. Furthermore, of thepolypeptides that bind to resins, these can be rank ordered by theirability to remain bound to the resin through stringent wash conditionswith increasing concentrations of NaCl. Those polypeptides found in the2000 mM NaCl samples have been able to remain bound through 1000 mM NaClwash conditions. It is widely accepted that any polypeptide which canremain bound to an ion exchange resin above 500 mM NaCl is considered tohave very high affinity for that resin. The banding pattern is similarbetween the two cation exchange resins supporting that the proposedmechanism. Likewise, the banding pattern is similar between the twoanion exchange resins, and represents a different sample set than thoseidentified by cation exchange. To rank order the individual polypeptidesidentified in any subset, LC/MS/MS is utilized.

As an exemplary dataset, the LC/MS/MS results identified the followingpolypeptides as binding to the Capto DEAE anion exchange resin at pH7.5: P39645, P37869, P80698, P80868, P21880, P80239, P50849, P12425,034669, P39138, P37871, P19669, P29727, P80643, 034981. P80879, P54716,P37477. As an exemplary dataset, the LC/MS/MS results identified thefollowing polypeptides as binding to the Poros XS cation exchange resinat pH 4.0: 034669, P19405, 031803, 005411, 031973, 031643, P80239,P26901. P08821, P80240, P49814, 034310, P0C178, 031925, P71014, P42111.

These polypeptides identified as having high binding affinity wereanalyzed for physicochemical properties based on their primary sequence.The net charge per amino acid was calculated based on primary sequenceacross the range of pH tested. As described herein, it is expected thatpolypeptides which bind tightly to anion exchange resins have a netcharge per amino acid below 0 across the pH range, and this wasgenerally demonstrated to be true. As described herein, it is expectedthat polypeptides which bind tightly to cation exchange resins have anet charge per amino acid above 0 across the pH range, and this wasgenerally demonstrated to be true. Any exception is expected to be dueto the fact that there is charge heterogeneity across the length of thesequence, and as described, net charge per amino acid does not alwayscapture that. This multiplexed screen identified a set of polypeptidesfrom a larger library based on their affinity to bind anion exchangeresin, and this result can be predicted based on the primary sequenceanalysis, as described herein.

In the Bacillus subtilis example of multiplexed purification, the set of168 nutritive polypeptide sequences was expressed without any type ofpurification tag. The cells were cultured in flasks, as described hereinand expressed and secreted the polypeptides into the growth media. Themethods tested included negative flocculation/precipitation, in whichthe impurities precipitate and the polypeptides that remain soluble rankthe highest. In these multiplexed purification studies, impurities arepresent in the form of soluble impurities (e.g. host cell proteins, DNA,phospholipids, and product-related impurities, such as isoforms oraggregated species), insoluble impurities, cells, or cellular debris(e.g. membrane fragments). Negative precipitation was performed prior toand following removal of insoluble impurities, cells, and cellulardebris centrifugation and further clarification by membrane filtration.

The set of solubly expressed and secreted polypeptides in the cellsuspension (prior to centrifugation and membrane filtration) andclarified supernatant (following centrifugation and membrane filtration)were rank ordered for their ability to associate with the flocculatingagents. Furthermore, the flocculating agents were rank ordered for theirability to associate with the impurities, 48 flocculating agents weretested at two different concentrations, as follows: Ammonium Bicarbonate(100 mM, 200 mM); Manganese Chloride (100 mM, 2(0 mM); Nickel Sulfate(100 mM, 200 mM); Sodium Citrate(100 mM, 200 mM); Lithium Acetate (100mM, 200 mM): Propylene Glycol (10% v/v, 20% v/v): Ammonium Nitrate (100mM, 200 mM); Potassium Chloride (I00 mM, 200 mM); Sodium Sulfate (100mM, 200 mM); Sodium Molybdate (100 mM, 200 mM); Acetic Acid (100 mM, 200mM); Chitosan MMW (0.1% w/v, 0.2% w/v); Ammonium Sulfate (100 mM, 200mM); Sodium Chloride (0.5M, 1.0 M); Zinc Sulfate (100 mM, 200 mM);Sodium Nitrate (100 mM, 200 mM); Citric Acid (100 mM, 200 mM); GuanidineHCl (0.6M, 1.2M); Ammonium Chloride (100 mM, 200 mM); Zinc Chloride (100mM, 200 mM); Potassium Carbonate (100 mM, 200 mM); Sodium Phosphate (100mM, 200 mM); Hydrochloric Acid (100 mM, 200 mM); PEG 1000 (5% w/v, 10%w/v); Calcium Chloride (100 mM, 200 mM); Iron Citrate (100 mM, 200 mM);Potassium Nitrate (100 mM, 200 mM); Sodium Propionate (100 mM, 200 mM);Potassium Hydroxide (100 mM, 200 mM); PEG 4000 (5% w/v, 10% w/v);Choline Chloride (100 mM, 200 mM); Copper Sulfate (100 mM, 200 mM);Potassium Phosphate (100 mM, 200 mM); Sodium Succinate (100 mM, 200 mM);Sodium Hydroxide (100 mM, 200 M); Triton X-100 (0.5% w/v, 1.0% w/v);Iron Chloride (100 mM, 200 mM); Iron Sulfate (100 mM, 200 mM);Deoxycholic Acid (0.5% w/v, 1.0% w/v); Sodium Thiocyanate (100 mM, 200mM); Ethanol (10% v/v, 20% v/v); Tween 80 (0.5% w/v, 1.0% w/v);Magnesium Chloride (100 mM, 200(M); Magnesium Sulfate (100 mM, 200 (mM);Sodium Carbonate (100 mM, 200 mM); Sodium Thiosulfate (100 mM, 200 mM);Isopropanol (10% v/v, 20% v/v): Urea (0.8M, 1.6M).

The cell suspension (prior to centrifugation and membrane filtration)and clarified supernatant (following centrifugation and membranefiltration) were distributed into a 96-well filter plate (300 μL perwell for the low flocculating agent concentration and 267 μL for thehigh flocculating agent concentration). These loads were diluted 0.1× or0.2× by adding 33 μL or 67 μL, respectively, of concentratedflocculating agent solutions. The resulting solution was mixed for 1hour at room temperature. Following mixing, the remaining solublematerial was separated from the insoluble material by centrifuging theliquid through the filterplate for collection in a 96 well plate below.All 192 samples were analyzed by Chip electrophoresis. Select sampleswere analyzed by SDS-PAGE. Select samples were analyzed by LC/MS/MS. Allanalytical assays are described herein.

SDS-PAGE results demonstrated that some conditions effectivelyprecipitated many polypeptides, indicating that the soluble polypeptidesin those conditions were rather soluble, and can be isolated in theseconditions. The polypeptides that were soluble in the variousprecipitation conditions were isolated from a larger set based on theirproperties in a purification process, which has implications for themanufacture, cost, development time, and eventual purity of thesepolypeptides. Some polypeptides are widely soluble across a range ofconditions due to their high charge, according the mechanism describedherein. To rank order the individual polypeptides identified in anysubset, LC/MS/MS is utilized.

As an exemplary dataset, the LC/MS/MS results demonstrated that thefollowing polypeptides were isolated due to their sustained solubilityin 100 mM Acetic Acid, pH 5.18: O34669, P54423, P21879, P10475, P28598,O31803, P40767, P17889, O34918, Q08352, P24327, P37871, O31973, P81101,P50849, P26901, P80700, O34385, P70960, P42111, P21880, P27876, P80868,P54716, O34313, O07603, O05411, P54531, O05497, P12425, O07921, P19405,Q06797, P02394, P24141, P09339, P37965, P07343, P37809, P0C178, P39824,P49814. P39632, P39773, P51777, P21883, O06989, P25152, P70961, O07593,O34310, P80860, P37437, P80698, P13243, P38494, P39645, P39148, O31398,P08821. P08877, O05268, P04957, P28366, P31103, P94421, P14949, P80864,P37869, P80240, P80859, O06993, O34666, O34714, P37546, Q9KWU4, 031605,P16616, P80239, O34788, P71014, P37571, P09124, P42971, O31925, P39793,P17865, P16263, P18429, P05653, P26908, P33166, O34499, P08750, P54602,Q45071. P12047, P42919, O34334, O34358, P39120, P39126, P00691, P14192,P22250, P37870, P39116, P54484, P54488, P54547, P56849, O31579, O34629,P30949, P54422, P54530, P54542, P96739.

As an exemplary dataset, the LC/MS/MS results demonstrated that thefollowing polypeptides were isolated due to their sustained solubilityin 100 mM Potassium Carbonate, pH 9.66: O34669, P54423, P21879, P24327,P40767, P17889, O31973, P10475, P28598, P80700, P37871, P80868, O31803,P81101, P70960, P27876, P19405, P28366, P71014, P26901, O34385, P21880,Q06797, P24141, P07343, P80698, P13243, P42971, P39793, O31643, P39071,O32210, P21468, P42199, P54531, P37965, P37809, P21883, P38494, P39148,P08877, P09124, P17865, P16263, P54602, P46906, O34918, Q08352, P42111,O05411, O05497, O07921, P02394, P09339, P49814, P39632, P37437, P39645,P08821, P04957, P31103, Q9KWU4, P80239, O34788, P18429, P05653, P26908,O34499, P08750, P12047, P37870, P54547, Q06796, Q45477, P25144, P46898,P40871, O31501, P21464, P21465, P40409.

As an exemplary dataset, the LC/MS/MS results demonstrated that thefollowing polypeptides were isolated due to their sustained solubilityin 100 mM Calcium Chloride, pH 7.50: O34669, P54423, P21879, O34918,O31803, P10475, P28598, P24327, P40767, P80700, P27876, P37871, O34385,P13243, Q08352, O07921, P17889, 031973, P80868, P26901, P24141, P80698,P02394, Q06797, P39148, P19405, P54531, P37965, P09339, P39645, O34788,P37571, O07909, P70960, P21880, P42971, P37809, P80239, Q45477, P94421,P81101, P07343, P39793, P39071, P38494, P17865, P42111, P12425, P39773,O06989, P80864, O05411, 005497, P25144, P0CI78, P39824, P25152, P70961,O31398, O05268, P37869, P80859, O32150, P39138, O31643, P21468, P42199,P21883, P09124, P49814, P05653, Q06796, O34313, P51777, O34310, O06993,O34666, O31925, P33166, P39634, P37808, P39779, P28366, P08877, P16263,P39632, P08821, P04957, 034499, P08750, P46898. P50849, P54716, P80860,P14949, P80240, Q45071, O34334, O34358, P39120, P39126. P20278, P53001,P54375, O06006, O06988, O34667, O34981, P08164. P19669, P30950, P37487,P45694, P81102, P71014, P54602, P46906, P31103, P18429, P26908. P12047,P40871, O07603, O34714, P37546, P42919. P00691, P22250, P39116, P54488,P40924, C0SP93, O31760, O32023, O32106, O32167, O34962, P12048, P25995,P28015, P28599, P34957, P35137, P37253, P37477, P37812, P37940, P46354,P49778, P54169, P54418. P54550, P54941, P80885, P94576, Q04796, Q06004.Q07868, Q9R911.

As an exemplary dataset, the LC/MS/MS results demonstrated that thefollowing polypeptides were isolated due to their sustained solubilityin 100 mM Iron Chloride, pH 4.54: P26901, O34669, O34918, P54423,O31803, P96657, O31973. P37871, O07921, O31643, Q06796. P17889, P80698,P80239, O05411, O07909, O31925, P20278, P71014, P21879, P10475, P80700,P27876, Q08352, P81101, P42111, P0C178, P39824, 032210, P28598, P24327,O34385, Q06797, P19405, P37571, P38494, O31398, P09124, P51777. P08821,P18429, O07593, P80868, P09339, P39645, O34788, O05268, P49814, P08877,P39632, P04957, P14949, P31103, O06746, O07555, P40767, P02394, P54531,P37965, P70960, P37809, P07343, P39773, P33166, P39634, P16263, P46898,P50849, P54716, P80240, Q45071, P53001, P54375, P26908, P42919, P40924,P14192, P54484, P56849, O06748, P12878, P21477. P32081, P46899, P50620,P54464.

These polypeptides identified as having high solubility were analyzedfor physicochemical properties based on their primary sequence. Thetotal charge per amino acid was calculated based on primary sequenceacross the range of pH tested. As described herein, it is expected thatthe most soluble polypeptides have a high total charge per amino acid,and this was generally demonstrated to be true. This multiplexed screenidentified a set of polypeptides from a larger library based on theiraffinity to bind anion exchange resin, and this result can be predictedbased on the primary sequence analysis, as described herein.

Multiplexed Purification: Precipitation & Flocculation.

Conventional biopharmaceutical protein purification methods used toremove cells and cellular debris include centrifugation,microfiltration, and depth filters. Filter aids, such as diatomaceousearth, can be used to enhance performance of these steps, but they arenot always effective and sometimes significantly bind the product ofinterest. Their use may also require the addition of a solid or ahomogeneous suspension that can be challenging as part of large-scalebiopharmaceutical operations.

Polymeric flocculants can be used to aid in the clarification ofmammalian cell culture process streams, but they can have limitations.For example, protamine sulfate preparations typically used as processingaids are limited in application due to concerns about inactivation ofthe protein of interest or product loss due to precipitation (Scopes.Protein Purification Principles and Practice 3rd edition. Cantor eds,22-43; 171 (1994)).

High quality reagents, such as that sold for medical use, can beexpensive. In certain instances, removal to very low levels be requiredto ensure there are no adverse effects in patients. For example,chitosan is not a well-defined reagent and there are concerns about itsconsistent performance in routine use in clarification applications.Multiple charged polymers, such as DEAE dextran, acrylamide-basedpolymers often used in waste-water treatment (NALCO Water Handbook.Section 2.1: Applications-Impurity Removal, 3rd ed., McGraw-Hill, 2009)and polyethylene amine (PEI) have been considered for use inclarification applications. With respect to the latter two types ofpolymers, the acrylamide reagents have the potential for contaminationwith toxic reagents and polyethylene amine, while a highly effectiveclarification reagent, is often contaminated with varying amounts ofethylenimine monomer, a suspected cancer agent (Scawen et al., Handbookof Enzyme Biotechnology 2nd edition. Wiseman eds.:15-53 (1985)).Moreover, many of these polymers, including PEI, tend to bind almostirreversibly to many chromatography resins, thereby limiting downstreamprocessing options. The regulatory and raw material reuse concernsassociated with these polymers have limited their application primarilyto academic studies.

Non-polymer based flocculants, such as alum and iron salts, have beenutilized in the wastewater treatment industry (NALCO Water Handbook,Section 2.1: Applications-Impurity Removal, 3rd ed., McGraw-Hill, 2009).These substances may appear to be non-useful in processing proteinproducts, because they may bind to the protein product or may catalyzechemical reactions resulting in modifications of the protein that couldaffect safety or efficacy.

In some cases, an entire library of proteins is tested in a multiplexedscreening experimental platform. The 168 nutritive polypeptide librarywas transfected and expressed in a multiplexed expression system inwhich a single growth condition was used to produce each polypeptide ina single container. This multiplexed expression system allows any set ofpolypeptide sequences to be tested in parallel for a wide range ofmanufacturability parameters, each of which can be used to rank orderthe set of polypeptides being examined. A set of manufacturabilityparameters includes expression level, polypeptide solubility, ability ofpolypeptide to be purified by chromatography, ability to resist thermaldenaturation, ability of polypeptide to digest, ability of polypeptideto be purified by resisting harsh treatments.

For E. coli multiplexed purification by precipitation, the set of 168nutritive polypeptide sequences was HIS8 tagged. The cells werecultured, as described herein, ruptured, and the solution was clarified,as described herein. This production resulted in a solution containingall of the polypeptides from the set which were both expressed andsoluble. That set of soluble polypeptides was passed over an IMACcolumn, and eluted, as described herein. This IMAC purificationeffectively isolated the solubly expressed nutritive polypeptides as aset by removing the majority of E. coli host cell proteins. The elutionfraction was concentrated and buffer exchanged into a low salt solutionbuffered near neutral pH before testing various purification methods.The methods tested include anion exchange chromatography, cationexchange chromatography, and negative precipitation, in which theimpurities precipitate and the polypeptides that remain soluble rank thehighest. In this case, impurities have been removed, so the polypeptidesare rank ordered amongst themselves. Additionally, the set of proteinswas tested for thermal stability, by heating, wherein the polypeptideswhich remain soluble after heating are more thermal stable than thosewhich precipitate.

The pre-treated group of polypeptides expressed by E. coli wasdistributed to 32 wells of a 96 well plate (4.7 μL of protein stock perwell at a total protein concentration of 43 g/L). Stock solutions wereadded to each well to create the following conditions: Control(NoAdditives): 42 mM Citrate/Phosphate, pH 7.1; 42 mM Citrate/Phosphate, pH6.5; 42 mM Citrate/Phosphate, pH 6.0; 42 mM Citrate/Phosphate, pH 5.6;42 mM Citrate/Phosphate, pH 5.0; 42 mM Citrate/Phosphate, pH 4.6; 42 mMCitrate/Phosphate, pH 4.3; 42 mM Citrate/Phosphate, pH 3.9; 42 mMCitrate/Phosphate, pH 3.7; 42 mM Citrate/Phosphate, pH 2.8; 75 mM TrisBase; 50 mM Na2CO3; 50 mM Piperazine Base; 100 mM sodium phosphatedibasic; 50 mM ethanolamine; 100 mM sodium phosphate monobasic; 100 mMMES Acid; 100 mM Sodium Acetate, pH 4.1; 100 mM MOPS Acid; 100 mM TrisHCl; 25 mM Acetic Acid; 25 mM Boric Acid; 25 mM Citric Acid; 50 mM PIPESAcid; 50 mM Succinic Acid; 1.2 M sodium sulfite; 1.5 M sodium sulfite;2.5 M Ammonium Sulfate; 3.5 M Ammonium Sulfate; 200 mM CaCl2; 60%methanol. Water was added such that each well contained a total of 40 uLof solution at 5 g/L. The plates were mixed for 30 minutes at roomtemperature, then centrifuged at 3,000 RCF for 10 minutes to pellet anyprecipitated protein. A sample was taken from each well for analysis.The 96 well plate sas then heated at 95° C. for 2 minutes. The plate wasagain centrifuged at 3,000 RCF for 10 minutes to pellet any precipitatedprotein, and a sample was taken from each well for analysis. All 64samples were analyzed by Bradford assay, and select samples wereanalyzed by chip electrophoresis, followed by LC/MS/MS. All analyticalassays are described herein. The measurements of total protein remainingin solution demonstrate that many conditions caused polypeptideprecipitation, indicating that a portion of the conditions tested wererigorous harsh conditions.

LC/MS/MS analysis was performed with four select samples, described inthe Table E9D. The detection of nutritive polypeptide in the solublefraction is noted with an X.

TABLE E9D Nutritive polypeptides detected in the soluble fraction ofselect conditions. Detection is noted with an X. 42 mM citrate/ 100 mM50 mM phosphate, sodium PIPES 2.5M pH 5.6, phosphate acid, AmmoniumSEQID heated monobasic heated sulfate SEQID-00105 X SEQID-00115 XSEQID-00302 X X X X SEQID-00304 X SEQID-00305 X X X X SEQID-00316 X XSEQID-00323 X X SEQID-00338 X X X X SEQID-00341 X X X X SEQID-00343 X XX X SEQID-00345 X X X X SEQID-00346 X X X SEQID-00352 X X X XSEQID-00354 X X X X SEQID-00356 X SEQID-00357 X X X SEQID-00485 X XSEQID-00495 X X X SEQID-00497 X X SEQID-00502 X X X X SEQID-00507 XSEQID-00509 X SEQID-00510 X X X X SEQID-00511 X X X SEQID-00515 XSEQID-00518 X SEQID-00521 X X SEQID-00522 X X X X SEQID-00525 X X X XSEQID-00528 X X SEQID-00529 X X SEQID-00533 X X SEQID-00537 X XSEQID-00540 X X X SEQID-00546 X X SEQID-00547 X X X SEQID-00553 X X X XSEQID-00555 X X SEQID-00559 X SEQID-00560 X X X SEQID-00564 X X X XSEQID-00570 X X X SEQID-00585 X X X X SEQID-00587 X X X SEQID-00592 X XX SEQID-00598 X X X SEQID-00601 X X X SEQID-00603 X SEQID-00605 X X XSEQID-00606 X X SEQID-00610 X SEQID-00613 X X X SEQID-00619 XSEQID-00622 X X SEQID-00623 X X X X SEQID-00631 X X X SEQID-00632 X X XX SEQID-00633 X X X SEQID-00641 X SEQID-00647 X X X SEQID-00648 X

LC/MS/MS data identified a number of soluble polypeptides in eachcondition. The different conditions tested across the screen represent anumber of different mechanisms of precipitation, and these differentconditions were able to identify different sets of polypeptides based ontheir different physicochemical properties. Based on the number ofpolypeptides which remained soluble, of the conditions examined byLC/MS/MS, the harshest condition is the 2.5 M ammonium sulfate conditionat room temperature. The polypeptides that were soluble in thatcondition were generally soluble in all three other conditions tested,with few exceptions. A large number of polypeptides were identified asbeing soluble after being heated to 95° C. for two minutes. In thisexperiment, a library of nutritive polypeptides was physically screenedfor solubility across a wide variety of conditions, and subsets ofsoluble peptides were identified within each condition.

Example 11 Selection of Amino Acid Sequences of Nutritive Polypeptidesfrom Amino Acid Sequence Libraries Based on Solvation Scores andAggregation Scores, and Other Sequence-Based Analyses

Solvation Score. The solvation score is a primary sequence-based metricfor assessing the hydrophilicity and potential solubility of a givenprotein. It is defined as the total free energy of solvation (i.e. thefree energy change associated with transfer from gas phase to a dilutesolution) for all amino acid side chains, assuming each residue weresolvated independently, normalized by the total number of residues inthe sequence. The side chain solvation free energies were foundcomputationally by calculating the electrostatic energy differencebetween a vacuum dielectric of 1 and a water dielectric of 80 (bysolving the Poisson-Boltzmann equation) as well as the non-polar, Vander Waals energy using a linear solvent accessible surface area model(D. Sitkoff. K. A. Sharp, B. Honig. “Accurate Calculation of HydrationFree Energies Using Macroscopic Solvent Models”. J. Phys. Chem. 98,1994). These solvation free energies correlate well with experimentalmeasurements. For amino acids with ionizable sidechains (Arg, Asp, Cys.Glu, His, Lys and Tyr), an average solvation free energy is based on therelative probabilities for each ionization state at the specified pH.The solvation score is effectively a measure of the solvation freeenergy assuming all polar residues are solvent exposed and non-polarresidues are solvent excluded upon folding.

Aggregation Score. The aggregation score is a primary sequence basedmetric for assessing the hydrophobicity and likelihood of aggregation ofa given protein. Using the Kyte and Doolittle hydrophobity scale (KyteJ, Doolitile R F (May 1982). “A simple method for displaying thehydropathic character of a protein”. J. Mol. Biol. 157 (1): 105-32),which gives hydrophobic residues positive values and hydrophilicresidues negative values, the effective hydrophobicity as a function ofsequence position is calculated using a moving average of 5 residuescentered around each residue. The aggregation score is found by summingall those average hydrophobicity values greater than 0 and normalizingby the total length of the protein. The underlying understanding is thataggregation is the result of two or more hydrophobic patches comingtogether to exclude water and reduce surface exposure, and thelikelihood that a protein will aggregate is a function of how denselypacked its hydrophobic (i.e., aggregation prone) residues are.

Charge Content.

The absolute or net charge per amino acid is calculated as a function ofpH and independently of the location of the residue within the protein.Given a pH value and the pKa of a titratable residue, theHenderson-Hasselbalch equation is solved to determine the relativeconcentrations of each titration state (e.g. −1 or 0 for the acidicresidue glutamate).

${pH} = \left. {pE}_{a} \middle| {\log_{10}\begin{pmatrix}\left\lbrack A^{*} \right\rbrack \\\lbrack{HA}\rbrack\end{pmatrix}} \right.$

The Henderson-Hasselbalch Equation

The average charge for that titratable residue is found by convertingthese relative concentrations into effective probabilities of beingcharged and multiplying by the charge and number of instances of thatamino acid. The net or absolute charge found from this procedure is thendivided by the number of amino acids to get the per amino acid value.

The residue types shown below in Table E11A are used with thecorresponding pKa values and relevant titration states. These pKa valuescome from the pKa table provided in the European Molecular Biology OpenSoftware Suite (Rice, P. Longden, I. and Bleasby. A. EMBOSS: TheEuropean Molecular Biology Open Software Suite. Trends in Genetics, 16,2000).

TABLE E11A Residue pKa Titration States Glutamate −4.1 −1, 0 Aspartate−3.9 −1, 0 Arginine −12.5 0, +1 Lysine −10.8 0, +1 Histidine −6.5 0, +1Cysteine −8.5 −1, 0 Tyrosine −10.1 −1, 0 C-terminus −3.6 −1, 0N-terminus −8.6 0, +1

Weighted Euclidean Distance.

To identity candidate proteins with a similar amino acid breakdown to aknown, clinically efficacious blend, a weighted Euclidean distance basedsearch strategy is used. In principle, this means computing the weightedpercent differences for each amino acid relative to the target aminoacid distribution, as defined by the following equation:

$\mspace{79mu} {{Distance} = \sqrt{\text{?}}}$?indicates text missing or illegible when filed

where AA is the set of all amino acids in the target distribution, x_(i)is the fraction by weight of amino acid i in the candidate proteinsequence, x_(i) ^(T) is the fraction by weight of amino acid i in thetarget amino acid distribution, and α_(i) is the relative weightassociated with amino acid i. The relative weights were applied toensure that large deviations from the most important amino acid targetswere appropriately penalized.

As an example, for treatment of sarcopenia, support of exercise, andstimulation of thermogenesis amino acid blends (given the relativeimportance of Leucine and the other two branched chain amino acids,Isoleucine and Valine) relative weights of 3:2:2 for Leucine, Valine,and Isoleucine were used. All other amino acids were given a relativeweight of 1.

Allergenicity.

The allergenicity score is a primary sequence based metric based on WHOrecommendations (fao.org/ag/agn/food/pdf/allergygm.pdf) for assessinghow similar a protein is to any known allergen, the primaryunderstanding being that high percent identity between a target and aknown allergen is likely indicative of cross reactivity. For a givenprotein, the likelihood of eliciting an allergic response is assessedvia a complimentary pair of sequence homology based tests. The firsttest determines the protein's percent identity across the entiresequence via a global-local sequence alignment to a database of knownallergens using the FASTA algorithm with the BLOSUM50 substitutionmatrix, a gap open penalty of 10, and a gap extension penalty of 2. Itis suggested that proteins with less than 50% global homology acrossboth sequences are unlikely to be allergenic (Goodman R. E. et al.Allergenicity assessment of genetically modified crops—what makes sense?Nat. Biotech. 26, 73-81 (2008); Aalberse R. C. Structural biology ofallergens. J. Allergy Clin. Immunol. 106, 228-238 (2000).). The secondtest assesses the local allergenicity along the protein sequence bydetermining the local allergenicity of all possible contiguous 80 aminoacid fragments via a global-local sequence alignment of each fragment toa database of known allergens using the FASTA algorithm with theBLOSUM50 substitution matrix, a gap open penalty of 10, and a gapextension penalty of 2. The highest percent identity of any 80 aminoacid window with any allergen is taken as the final score for theprotein of interest. The WHO guidelines suggest using a 35% identitycutoff. The custom database comprises pooled allergen lists collected bythe Food Allergy Research and Resource Program (allergenonline.org/),UNIPROT annotations (uniprot.org/docs/allergen), and the StructuralDatabase of Allergenic Proteins (SDAP,fermi.utmb.edu/SDAPisdap_lnk.html). This database includes all currentlyrecognized allergens by the International Union of ImmunologicalSocieties (IUIS, allergen.org/) as well as a large number of additionalallergens not yet officially named.

Toxicity/Nonalergenicity/Antinutricity.

The toxicity, nonallergenicity, and anti-nutricity of a protein are allassessed similarly, by determining the protein's percent identity todatabases of known toxic, nonallergenic, and protease inhibitoryproteins, respectively. The toxicity and anti-nutritive qualities areassumed to be a function of the whole protein (i.e., a fragment of aknown toxic protein will not be toxic), as their toxic and inhibitorymechanisms of action are often structural in nature (Huntington J., ReadR, Carrell R. “Structure of a serpin-protease complex shows inhibitionby deformation”. Nature 407 (2000): 923-6; Van den Born H. K. et al.Theoretical analysis of the structure of the peptide fasciculin and itsdocking to acetylcholinesterase. Protein Sci. 4 (1995): 703-715.: andHarel M. Crystal structure of an acetylcholinesterase-fasciculincomplex: interaction of a three-fingered toxin from snake venom with itstarget. Structure. 3 (1995): 1355-1366.). Given that protein structureis a function of the entire protein sequence, a global-global alignmentis performed of the protein of interest against the two respectivedatabases using the FASTA algorithm with the BLOSUM50 substitutionmatrix, a gap open penalty of 10, and a gap extension penalty of 2. Acut off of 35% can be used. While it does not provide specificinstructions of how to avoid toxic/antinutritive polypeptides, referenceDelaney B. et al. Evaluation of protein safety in the context ofagricultural biotechnology. Food. Chem. Toxicol. 46 (2008: S71-S97suggests that one should avoid both known toxic and antinutritivepolypeptides when assessing the safety of a possible food protein.

The nonallergenicity of a protein is related to its likelihood ofeliciting an allergenic response upon exposure (similar to but oppositeof allergenicity). Specifically, the human immune system is exposed to amultitude of possible allergenic proteins on a regular basis, and hasthe intrinsic ability to determine self from non-self. The exact natureof this ability is not always clear, and there are many diseases thatarise as a result of the failure of the body to differentiate self fromnon-self (e.g. arthritis). Nonetheless, the understanding is thatproteins that look (i.e. share a large degree of sequence homology to) alot like nonallergenic (i.e., human) proteins are less likely to elicitan immune response. In particular, it has been shown that for someprotein families with known allergenic members (tropomyosins,parvalbumins, caseins), those proteins that bear more sequence homologyto their human counterparts relative to known allergenic proteins, arenot thought to be allergenic (Jenkins J. A. et al. Evolutionary distancefrom human homologs reflects allergenicity of animal food proteins. J.Allergy Clin Immunol. 120 (2007): 1399-1405.) For a given protein, thenonallergenicity score is measured by determining the maximum percentidentity of the protein to a database of human proteins from aglobal-local alignment using the FASTA algorithm with the BLOSUM50substitution matrix, a gap open penalty of 10, and a gap extensionpenalty of 2. Cutoffs can vary. For example, Jenkins J. A. et al.(Evolutionary distance from human homologs reflects allergenicity ofanimal food proteins. J. Allergy Clin Immunol. 120 (2007): 1399-1405)claim that proteins with a sequence identity to a human protein above˜62% are less likely to be allergenic.

Example 12 Expression of Nutritive Polypeptides

The lists below include all the nutritive protein sequences that wereexpressed in Escherichia coli, Bacillus, Aspergillus niger, andmammalian cells. In E. coli, the proteins were detected in either wholecell lysates or in the soluble fraction of the cell lysate. In Bacillus,expression was detected in either cell lysates or secreted supernatantsof Bacillus subtilis or Bacillus megaterium. In Aspergillus niger,proteins were secreted from the fungus and detected in the supernatant.For proteins expressed in mammalian cells, they were expressed in eitherin Chinese Hamster Ovarian-S strain (CHO-S) or Human Embryonic Kidney293F strain (HEK293F). Expression was measured by the following metrics:mass spectrometry spectrum counts for protein expression data acquiredfrom LC-MS/MS in pooled library. SDS-PAGE, Chip Electrophoresis, dotblot, Western blot and ELISA for individual protein expression asdescribed above.

The following nutritive polypeptides were detected in either whole celllysates or in the soluble fraction of the cell lysates of Escherichiacoli: SEQID-00001, SEQID-00002, SEQID-00003, SEQID-00004, SEQID-00005,SEQID-00007, SEQID-00008, SEQID-00009, SEQID-00011, SEQID-00012,SEQID-00013, SEQID-00014, SEQID-00015, SEQID-00016, SEQID-00020,SEQID-00021, SEQID-00024, SEQID-00025, SEQID-00027, SEQID-00028,SEQID-00029, SEQID-00030, SEQID-00031., SEQID-00033, SEQID-00043,SEQID-00049, SEQID-00051, SEQID-00052, SEQID-00053, SEQID-00054,SEQID-00055, SEQID-00057, SEQID-00059, SEQID-00060, SEQID-00061,SEQID-00068, SEQID-00070, SEQID-00071, SEQID-00073 SEQID-00074,SEQID-00075, SEQID-00076, SEQID-00077, SEQID-00078. SEQID-00083,SEQID-00084, SEQID-00085, SEQID-00086, SEQID-00087, SEQID-00088,SEQID-00090, SEQID-00091, SEQID-00092, SEQID-00093, SEQID-00098,SEQID-00099, SEQID-00100, SEQID-00101, SEQID-00102, SEQID-00103,SEQID-00104, SEQID-00105, SEQID-00106, SEQID-00107, SEQID-00108,SEQID-00110, SEQID-00112, SEQID-00113, SEQID-001115, SEQID-00116,SEQID-00117, SEQID-00118, SEQID-00123, SEQID-00124, SEQID-00128,SEQID-00130, SEQID-00131, SEQID-00132, SEQID-00134, SEQID-00137,SEQID-00139, SEQID-00140, SEQID-00141, SEQID-00142, SEQID-00143,SEQID-00145. SEQID-00146, SEQID-00148, SEQID-00150, SEQID-00151,SEQID-00152, SEQID-00153, SEQID-00154, SEQID-00155, SEQID-00157,SEQID-00158, SEQID-00159, SEQID-00162, SEQID-00166, SEQID-00169,SEQID-00175, SEQID-00193, SEQID-00194, SEQID-00195, SEQID-00196,SEQID-00197, SEQID-00198, SEQID-00199, SEQID-00200, SEQID-00201,SEQID-00202, SEQID-00203, SEQID-00204, SEQID-00205, SEQID-00211,SEQID-00212, SEQID-00213, SEQID-00214, SEQID-00215, SEQID-00216,SEQID-00218, SEQID-00219, SEQID-00220, SEQID-00221, SEQID-00223,SEQID-00224, SEQID-00225, SEQID-00226. SEQID-00227, SEQID-00228,SEQID-00230, SEQID-00232, SEQID-00233, SEQID-00234, SEQID-00235,SEQID-00236, SEQID-00237, SEQID-00239, SEQID-00240, SEQID-00241,SEQID-00264, SEQID-00265, SEQID-00266, SEQID-00267, SEQID-00268,SEQID-00269, SEQID-00270, SEQID-00271, SEQID-00273, SEQID-00274,SEQID-00275, SEQID-00276, SEQID-00284, SEQID-00287, SEQID-00297,SEQID-00298, SEQID-00299, SEQID-00302, SEQID-00303, SEQID-00304,SEQID-00305, SEQID-00306, SEQID-00307, SEQID-00309, SEQID-00318,SEQID-00322, SEQID-00325, SEQID-00326, SEQID-00327, SEQID-00328.SEQID-00329, SEQID-00332, SEQID-00335, SEQID-00336, SEQID-00337,SEQID-00338, SEQID-00341, SEQID-00343, SEQID-00344, SEQID-00345,SEQID-00346, SEQID-00349, SEQID-00350, SEQID-00352, SEQID-00353,SEQID-00354, SEQID-00355, SEQID-00356, SEQID-00357, SEQID-00358,SEQID-00359, SEQID-00360, SEQID-00362, SEQID-00363, SEQID-00408,SEQID-00409, SEQID-00415, SEQID-00416, SEQID-00418, SEQID-00424,SEQID-00481, SEQID-00482, SEQID-00483, SEQID-00484, SEQID-00485,SEQID-00486, SEQID-00487, SEQID-00488, SEQID-00489, SEQID-00490,SEQID-00491, SEQID-00492. SEQID-00493, SEQID-00494, SEQID-00495,SEQID-00496, SEQID-00497, SEQID-00498, SEQID-00499, SEQID-00500,SEQID-00501, SEQID-00502, SEQID-00503, SEQID-00504, SEQID-00505,SEQID-00506, SEQID-00507, SEQID-00508, SEQID-00509, SEQID-00510,SEQID-00511, SEQID-00512, SEQID-00513, SEQID-00514, SEQID-00515,SEQID-00516, SEQID-00517, SEQID-00518, SEQID-00519, SEQID-00520,SEQID-00521, SEQID-00522, SEQID-00523, SEQID-00524, SEQID-00525,SEQID-00526, SEQID-00527, SEQID-00528, SEQID-00529, SEQID-00530,SEQID-00531, SEQID-00532, SEQID-00533, SEQID-00534, SEQID-00535,SEQID-00536, SEQID-00537, SEQID-00538, SEQID-00539, SEQID-00540,SEQID-00541, SEQID-00542, SEQID-00543, SEQID-00544, SEQID-00545,SEQID-00546, SEQID-00547, SEQID-00548, SEQID-00549, SEQID-00550,SEQID-00551, SEQID-00552, SEQID-00553, SEQID-00554, SEQID-00555,SEQID-00556, SEQID-00557, SEQID-00558, SEQID-00559, SEQID-00560,SEQID-00561, SEQID-00562, SEQID-00563, SEQID-00564, SEQID-00565,SEQID-00566, SEQID-00567, SEQID-00568, SEQID-00569, SEQID-00570,SEQID-00571, SEQID-00572, SEQID-00573, SEQID-00574, SEQID-00575,SEQID-00576, SEQID-00577, SEQID-00578, SEQID-00579, SEQID-00580,SEQID-00581, SEQID-00582, SEQID-00583, SEQID-00584, SEQID-00585,SEQID-00586, SEQID-00587, SEQID-00588, SEQID-00589, SEQID-00590,SEQID-0059 I. SEQID-00592, SEQID-00593, SEQID-00594, SEQID-00595,SEQID-00596, SEQID-00597, SEQID-00598, SEQID-00599, SEQID-00600,SEQID-00601, SEQID-00602, SEQID-00603, SEQID-00604, SEQID-00605,SEQID-00606. SEQID-00607, SEQID-00608, SEQID-00609, SEQID-00610,SEQID-006 ii, SEQID-00612, SEQID-00613, SEQID-00614, SEQID-00615,SEQID-00616, SEQID-00617, SEQID-00618, SEQID-00619, SEQID-00620,SEQID-00621, SEQID-00622, SEQID-00623, SEQID-00624, SEQID-00625,SEQID-00626, SEQID-00627, SEQID-00628, SEQID-00629, SEQID-00630,SEQID-00631, SEQID-00632, SEQID-00633, SEQID-00634, SEQID-00635,SEQID-00636, SEQID-00637, SEQID-00638, SEQID-00639, SEQID-00640,SEQID-00641, SEQID-00642, SEQID-00643, SEQID-00644, SEQID-00645,SEQID-00646, SEQID-00647, SEQID-00648. SEQID-00669, SEQID-00670,SEQID-00671, SEQID-00672, SEQID-00673, SEQID-00674, SEQID-00675,SEQID-00676, SEQID-00677, SEQID-00678, SEQID-00679, SEQID-00680,SEQID-00681, SEQID-00682, SEQID-00716, SEQID-00717, SEQID-00718,SEQID-00719, SEQID-00720, SEQID-00723, SEQID-00724, SEQID-00725,SEQID-00)726, SEQID-00727, SEQID-00728, SEQID-00729, SEQID-00730,SEQID-00731, SEQID-00732, SEQID-00734, SEQID-00735, SEQID-00736,SEQID-00737, SEQID-00738, SEQID-00739, SEQID-00740, SEQID-00741,SEQID-00742, SEQID-00743, SEQID-00744, SEQID-00745, SEQID-00746.SEQID-00747, SEQID-00748, SEQID-00749, SEQID-00750, SEQID-00751,SEQID-00752, SEQID-00753, SEQID-00754, SEQID-00755, SEQID-00756,SEQID-00757, SEQID-00758, SEQID-00759, SEQID-00760, SEQID-00761,SEQID-00763, SEQID-00765, SEQID-00766, SEQID-00767, SEQID-00768,SEQID-00769, SEQID-00770, SEQID-00771, SEQID-00772, SEQID-00773,SEQID-00774, SEQID-00775, SEQID-00777, SEQID-00778, SEQID-00780,SEQID-00781, SEQID-00782, SEQID-00783, SEQID-00784, SEQID-00785,SEQID-00786, SEQID-00787, SEQID-00788, SEQID-00789, SEQID-00790,SEQID-00791, SEQID-00792, SEQID-00793, SEQID-00794, SEQID-00795,SEQID-00796, SEQID-00797, SEQID-00798, SEQID-00799, SEQID-00801,SEQID-00802, SEQID-00803, SEQID-00804, SEQID-00805, SEQID-00806,SEQID-00807, SEQID-00808, SEQID-00809, SEQID-00810, SEQID-00811,SEQID-00812, SEQID-00813, SEQID-00814, SEQID-00815, SEQID-00816,SEQID-00817. SEQID-00818, SEQID-00819, SEQID-00820, SEQID-00821,SEQID-00822, SEQID-00823. SEQID-00824, SEQID-00825, SEQID-00826,SEQID-00827, SEQID-00828, SEQID-00829, SEQID-00830, SEQID-00831,SEQID-00832, SEQID-00833, SEQID-00834, SEQID-00835, SEQID-00836,SEQID-00837.

The following nutritive polypeptides were detected in either celllysates or secreted supernatants of Bacillus subtilis or Bacillusmegaterium: SEQID.-00003, SEQID-00004, SEQID-00005, SEQID-00087,SEQID-00099, SEQID-00102, SEQID-00103, SEQID-00105. SEQID-00115,SEQID-00218, SEQID-00220, SEQID-00223, SEQID-00226, SEQID-00236.SEQID-00240, SEQID-00267, SEQID-00271, SEQID-00276, SEQID-00297,SEQID-00298, SEQID-00299, SEQID-00302, SEQID-00303, SEQID-00304,SEQID-00305, SEQID-00306, SEQID-00307, SEQID-00309, SEQID-00318,SEQID-00322, SEQID-00325, SEQID-00326, SEQID-00327, SEQID-00328,SEQID-00329, SEQID-00330, SEQID-00332, SEQID-00335, SEQID-00336,SEQID-00337, SEQID-00338, SEQID-00340, SEQID-00341, SEQID-00343,SEQID-00344, SEQID-00345, SEQID-00346, SEQID-00349, SEQID-00350,SEQID-00352. SEQID-00353, SEQID-00354, SEQID-00355, SEQID-00356,SEQID-00357, SEQID-00358, SEQID-00359, SEQID-00360, SEQID-00361,SEQID-00362, SEQID-00363, SEQID-00374, SEQID-00389, SEQID-00398,SEQID-00403, SEQID-00404, SEQID-00405, SEQID-00407, SEQID-00409,SEQID-00415, SEQID-00416, SEQID-00417, SEQID-00418, SEQID-00419,SEQID-00420, SEQID-00421, SEQID-00424, SEQID-00481I, SEQID-00482,SEQID-00483, SEQID-00484, SEQID-00485, SEQID-00486, SEQID-00487,SEQID-00488, SEQID-00489. SEQID-00490, SEQID-00491, SEQID-00492,SEQID-00493, SEQID-00494, SEQID-00495. SEQID-00496, SEQID-00497,SEQID-00498, SEQID-00499, SEQID-00500, SEQID-00501, SEQID-00502,SEQID-00503, SEQID-00504, SEQID-00505, SEQID-00506, SEQID-00507,SEQID-00508, SEQID-00509, SEQID-00510, SEQID-00511, SEQID-00512,SEQID-00513, SEQID-00514, SEQID-00515, SEQID-00516, SEQID-00517,SEQID-00518, SEQID-00519, SEQID-00520, SEQID-00521, SEQID-00522,SEQID-00523, SEQID-00524, SEQID-00525, SEQID-00526, SEQID-00527,SEQID-00528, SEQID-00529, SEQID-00530, SEQID-00531. SEQID-00532,SEQID-00533, SEQID-00534, SEQID-00535, SEQID-00536, SEQID-00537,SEQID-00538, SEQID-00539, SEQID-00540, SEQID-00541, SEQID-00542,SEQID-00543, SEQID-00544, SEQID-00545, SEQID-00546, SEQID-00547,SEQID-00548, SEQID-00549, SEQID-00550, SEQID-00551, SEQID-00552,SEQID-00553, SEQID-00554, SEQID-00555, SEQID-00556, SEQID-00557,SEQID-00558, SEQID-00559, SEQID-00560, SEQID-00561, SEQID-00562,SEQID-00563, SEQID-00564, SEQID-00565, SEQID-00566, SEQID-00567,SEQID-00568, SEQID-00569, SEQID-00570, SEQID-00571, SEQID-00572,SEQID-00573, SEQID-00574, SEQID-00575, SEQID-00576, SEQID-00577,SEQID-00578, SEQID-00579, SEQID-00580, SEQID-00581, SEQID-00582,SEQID-00583, SEQID-00584, SEQID-00585, SEQID-00586, SEQID-00587,SEQID-00588, SEQID-00589, SEQID-00590, SEQID-00591, SEQID-00592,SEQID-00593, SEQID-00594, SEQID-00595, SEQID-00596, SEQID-00597,SEQID-00598, SEQID-00599, SEQID-00600, SEQID-00601, SEQID-00602,SEQID-00603, SEQID-00604, SEQID-00605, SEQID-00606, SEQID-00607,SEQID-00608, SEQID-00609, SEQID-00610, SEQID-00611, SEQID-00612,SEQID-00613, SEQID-00614, SEQID-00615. SEQID-00616, SEQID-00617,SEQID-00618, SEQID-00619, SEQID-00620, SEQID-00621, SEQID-00622,SEQID-00623, SEQID-00624, SEQID-00625, SEQID-00626, SEQID-00627,SEQID-00628, SEQID-00629, SEQID-00630, SEQID-00631, SEQID-00632,SEQID-00633, SEQID-00634, SEQID-00635, SEQID-00636, SEQID-00637,SEQID-00638, SEQID-00639, SEQID-00640, SEQID-00641, SEQID-00642,SEQID-00643, SEQID-00644, SEQID-00645, SEQID-00646, SEQID-00647,SEQID-00648, SEQID-00653, SEQID-00654, SEQID-00655, SEQID-00656,SEQID-00657, SEQID-00659, SEQID-00660, SEQID-00664, SEQID-00668.SEQID-00670, SEQID-00671, SEQID-00672, SEQID-00673, SEQID-00674,SEQID-00675, SEQID-00676, SEQID-00678, SEQID-00679, SEQID-00680,SEQID-00681, SEQID-00682, SEQID-00690, SEQID-00710, SEQID-00711,SEQID-00712, SEQID-00713, SEQID-00714, SEQID-00715, SEQID-00716,SEQID-00717, SEQID-00718, SEQID-00719, SEQID-00720, SEQID-00723,SEQID-00724, SEQID-00725, SEQID-00726, SEQID-00727, SEQID-00728,SEQID-00729, SEQID-00730, SEQID-00731, SEQID-00734, SEQID-00735,SEQID-00736, SEQID-00737, SEQID-00738, SEQID-00739, SEQID-00740,SEQID-00741, SEQID-00742. SEQID-00743, SEQID-00744, SEQID-00745,SEQID-00746, SEQID-00747, SEQID-00748, SEQID-00749, SEQID-00750,SEQID-00751, SEQID-00752, SEQID-00753, SEQID-00754, SEQID-00755,SEQID-00756, SEQID-00757, SEQID-00758, SEQID-00759, SEQID-00760,SEQID-00761, SEQID-00763, SEQID-00765, SEQID-00766, SEQID-00767,SEQID-00768, SEQID-00769, SEQID-00770, SEQID-00771, SEQID-00772,SEQID-00773, SEQID-00774, SEQID-00775, SEQID-00777, SEQID-00778,SEQID-00780, SEQID-00781, SEQID-00782, SEQID-00783, SEQID-00784,SEQID-00785, SEQID-00786, SEQID-00787, SEQID-00788, SEQID-00789,SEQID-00790, SEQID-00791, SEQID-00792, SEQID-00793, SEQID-00794,SEQID-00795, SEQID-00796, SEQID-00797, SEQID-00798, SEQID-00799,SEQID-00800, SEQID-00801, SEQID-00802, SEQID-00803, SEQID-00804,SEQID-00805 SEQID-00806, SEQID-00807, SEQID-00808, SEQID-00809,SEQID-00810, SEQID-00811, SEQID-00812, SEQID-00813 SEQID-00814,SEQID-00815, SEQID-00816, SEQID-00817 SEQID-00818. SEQID-00819,SEQID-00820, SEQID-00821, SEQID-00822, SEQID-00823, SEQID-00824,SEQID-00825, SEQID-00826, SEQID-00827, SEQID-00828, SEQID-00829,SEQID-00830, SEQID-00831, SEQID-00832, SEQID-00833, SEQID-00834,SEQID-00835, SEQID-00836, SEQID-00837.

The following nutritive polypeptides were detected from the secretedsupernatant of Aspergillus niger SEQID-00087, SEQID-00103, SEQID-00105,SEQID-00112, SEQID-00115, SEQID-00218, SEQID-00298, SEQID-00341,SEQID-00352, SEQID-00354, SEQID-00363, SEQID-00406, SEQID-00409,SEQID-00415, SEQID-00416, SEQID-00417, SEQID-00418, SEQID-00419,SEQID-00420, SEQID-00421, SEQID-00424, SEQID-00552, SEQID-00554.

The following nutritive polypeptides were expressed in the mammaliancell lines Chinese Hamster Ovarian-S strain (CHO-S) or Human EmbryonicKidney 293F strain (HEK293F): SEQID-00001, SEQID-00103, SEQID-00105,SEQID-00298.

Example 13 Expression of Nutritive Polypeptides in E. coli Bacteria

A nutritive polypeptide sequence library was generated from ediblespecies and screened to demonstrate nutritive polypeptide expression inE. coli.

Gene Synthesis & Plasmid Construction.

All genes were made synthetically by either Life Technologies/GeneArt orDNA2.0, and optimized for expression in Escherichia coli. The genes werecloned into pET15b (EMD MilliporetNovagen) using the NdeI-BamHIrestriction sites within the multiple cloning site (therefore containingan amino-terminal MGSSHHHHHHSSGLVPRGSH tag), or cloned into theNcoI-BamHI sites (therefore removing the amino terminal tag on theplasmid) using primers to include an amino terminal tag containingMGSHHHHHHHH or MGSHHHHHHHHSENLYFQG, pET15b contains a pBR322 origin ofreplication, a lac-controlled T7 promoter, and a bla gene conferringresistance to carbenicillin. For manually cloned fragments, inserts wereverified by Sanger sequencing using both the T7 promoter primer and theT7 terminator primer. For the secreted constructs, the genes were clonedinto pJ444 vector (DNA 2.0, USA) upstream of T5 terminator withC-terminal HHHHHHHH tag and DsbA signal peptide(ATGAAAAAGATTTGGCTGCCTGGGCTGGTTTAGTITAGCGTTTAGCGCATCGG CG) inN-terminal.

Strain Construction. T7 Express Competent E. coli was purchased from NewEngland Biolabs and was used as the parent strain. T7 Express is anenhanced BL21 derivative which contains the T7 RNA polymerase in the lacoperon, while still lacking the Lon and OmpT proteases. The genoptype ofT7 Express is: fhuA2 lacZ::T7 gene1 [Ion] ompT gal sulA11R(mcr-73::miniTn10-TetS)2 [dcm] R(zgb-210::Tn10-TetS) endA1 Δ(mcrC-mrr)114::IS10. For secreted constructs, CGSC 5610 (Yale E. coli geneticstock center, USA) was used for the study. The genotype of CGSC 5610 isF−, lacY1 or Δ(cod-lacI)6, glnV44(AS), galK2(Oc), galT22, λ-, e 14-,mcrA0, rfbC1, metB1, mcrB1, hsdR2. Roughly 1 ng of purified plasmid DNAdescribed above was used to transform chemically competent T7 Expressand single colonies were selected on LB agar plates containing 100 mg/lcarbenicillin after roughly 16 hr of incubation at 37° C. Singlecolonies were inoculated into liquid LB containing 100 mg/lcarbenicillin and grown to a cell-density of OD600 nm=0.6, at whichpoint, glycerol was supplemented to the medium at 10% (v/v) and analiquot was taken for storage in a cryovial at −80° C.

Expression Testing.

Expression cultures were grown in LB medium (10 g/l NaCl, 10 g/ltryptone, and 5 g/l yeast extract) or in BioSilta EnBase medium andinduced with isopropyl A-D-1-thiogalactopyranoside (IPTG). Forexpression testing in LB media, a colony or stab from a glycerol stockwas inoculated into 3 ml LB supplemented with 100 mg/l carbenicillin andgrown overnight (roughly 16 hr) at 37° C. and 250 rpm. The next morning,the cell-density (spectrophotometrically at OD600 nm) was measured anddiluted back to OD6(H)nm=0.05 into 3 ml LB medium supplemented withcarbenicillin and grown at 37° C. and 250 rpm. At OD600 nm=0.8±0.2 thecultures were induced with 1 mM IPTG. Heterologous expression wasallowed to proceed for 2 hr at 37° C. and 250 rpm, at which point thecultures were terminated. The terminal cell-density was measured. Forexpression with Enbase media, a colony or stab from a glycerol stock wasinoculated into 3 ml LB with 100 mg/l carbenicillin and transferred toEnbase media with 100 mg/l carbenicillin and 600 mU/l of glucoamylase atOD600=0.1 and grown overnight at 37° C. and 250 rpm and induced with 1mM IPTG next day. Heterologous expression was allowed for 24 hours at37° C. and 250 rpm, at which point the cultures were terminated. Theterminal cell-density was measured and the cells were harvested bycentrifugation (3000 rpm, 10 min, RT). To determine intracellularproduction the cells were lyzed with B-PER (Pierce) according tomanufacturer's protocol and then assayed to measure protein of interest(POI). To determine the levels of secreted protein, 0.5-ml aliquots ofthe culture supernatants were filtered by a 0.22 μm filter. Thefiltrates were then assayed to determine the levels of secreted proteinof interest (POI).

Fermentation. The intracellular soluble proteins SEQID-00105,SEQID-00240, SEQID-00338, SEQID-00341, SEQID-00352, SEQID-00363,SEQID-00423, SEQID-00424, SEQID-00425, SEQID-00426, SEQID-00429,SEQID-00559, and SEQID-00587 were expressed in E. coli host cells NEB T7Express (New England BioLabs) in 20 and/or 250 L fermentations. Thefermentation occurred in a carbon and nitrogen rich media containing:Yeast Extract, Soy Hydrolysate, Glycerol, Glucose, and Lactose. Thefermentation occurred at 30° C. and induction occurred when the Glucosepresent in the media was exhausted and Lactose became the primary carbonsource sugar. The fermentation process time generally lasted 24-26 hrs.Fermentation run parameters were controlled at a pH of 6.9, temperatureof 30° C., and a percent dissolved oxygen of 35%. The culture wassupplemented with a Glycerol based feed in the later stages of theculture duration. Harvest occurred when the cells entered stationaryphase and no longer required oxygen supplementation to maintain the 35%set point.

Nutritive Polypeptide Library Gene Synthesis & Plasmid Construction.

Genes encoding for 168 different edible species polypeptide sequenceswere generated as linear fragments and codon-selected for expression inEscherichia coli. In some cases, a single linear fragment contained twoor more nucleic acid sequences encoding two or more distinct polypeptidesequences that had a flanking 5′ NdeI restriction site and 3′ BamHIrestriction site. All linear fragments were combined at equal molarconcentrations. The linear fragments were digested with NdeI and BamHIand the digested mixture was cloned into pET1Sb (EMD Millipore/Novagen)using primers to include an amino terminal tag containing MGSHHHHHHHHand NdeI-BamHI restriction sites, pET15b contains a pBR322 origin ofreplication, a lac-controlled T7 promoter, and a bla gene conferringresistance to carbenicillin. For cloned fragments, inserts were verifiedby Sanger sequencing using both the T7 promoter primer and the T7terminator primer.

168 Nutritive Polypeptide Library Strain Construction.

T7 Express Competent E. coli (New England Biolabs) was used as theparent strain. T7 Express is an enhanced BL21 derivative which containsthe T7 RNA polymerase in the lac operon, while lacking the Lon and OmpTproteases. The genotype of T7 Express is: fhuA2 lacZ::T7 gene1 [Ion]ompT gal sulA11 R(mcr-73::miniTn10-TetS)2 [dcm] R(zgb-210::Tn10-TetS)endA1 Δ(mcrC-mrr) 114::IS10. For secreted constructs, CGSC 5610 (Yale E.coli genetic stock center, USA) was used. The genotype of CGSC 5610 isF−, lacYI or A(cod-lacI) 6, glnV44(AS), galK2(Oc), galT22, λ−, e14−,mcrA0, rfbC1, metB1, mcrB1, hsdR2. Approximately 10 ng of ligated DNAmixture were transformed into chemically competent T7 Express and singlecolonies were selected on LB agar plates containing 100 mg/lcarbenicillin after roughly 16 hr of incubation at 37° C. Multipletransformations were done and approximately 1000 colonies were pooledtogether and suspended into LB medium. The DNA from 50-100 colonies wassequenced to determine the diversity of the generated library.

168 Nutritive Polypeptide Library Expression Testing.

The colony mixtures resuspended in LB medium were initially grown in 3ml of LB medium (10 g/l NaCl, 10 g/l tryptone, and 5 g/l yeast extract)with 100 mg/l carbenicillin, then transferred to BioSilta Enbase mediawith 100 mg/l carbenicillin and 600 mU/1 of glucoamylase at OD600=0.1,grown overnight at 37° C. and 250 rpm and induced with 1 mM IPTG nextday. Heterologous expression was allowed for 24 hours at 37° C. and 250rpm, at which point the cultures were terminated. The terminalcell-density was measured and the cells were harvested by centrifugation(3000 rpm, 10 min, RT). To determine intracellular production the cellswere lysed using a microfluidizer and the soluble fraction was purifiedin 5 ml Nickel Affinity column according to manufacturer's protocol andthen assayed using LC-MS/MS to identify the proteins that were expressedas described below. 114/168 different proteins were successfully solublyexpressed in E. coli based on MS spectral count. Based on this result,certain genes were individually cloned and tested for intracellularsoluble expression in E. coli.

Fungal Nutritive Polypeptides Expressed in E. coli Strain Backgrounds.

Four strains were used to express fungal nutritive polypeptides: T7Express, Shuffle T7, and Shuffle T7 Express from New England Biolabs;and Origami B(DE3) from EMD Millipore.

T7 Express is an enhanced BL21 derivative which contains the T7 RNApolymerase in the lac operon, while lacking the Lon and OmpT proteases.The genotype of T7 Express is: fhuA2 lacZ::T7 gene1 [Ion] ompT galsulA11 R(mcr-73::miniTn10-TetS)2 [dcm] R(zgb-210::Tn10-TetS) endA1Δ(mcrC-mrr)114::IS10.

Shuffle T7 is a K12 derivative strain that promotes cytoplasmicdisulfide bond formation and expresses a chromosomal copy of T7 RNAP.The genotype of Shuffle T7 is F′ lac, pro, lacIQ/Δ(ara-leu)7697 araD139fhuA2 lacZ::T7 gene1 Δ(phoA)Pvul phoR ahpC* galE (or U) galKλatt::pNEB3-r1-cDsbC (SpecR lacIq) ΔtrxB rpsL150(StrR) Δgor Δ(malF)3.

Shuffle T7 Express is a BL21 derivative strain that promotes cytoplasmicdisulfide bond formation and expresses a chromosomal copy of T7 RNAP.The genotype of Shuffle T7 Express is thuA2 lacZ::T7 gene1 [Ion] ompTahpC gal λatt::pNEB3-r1-cDsbC (SpecR, lacIq) ΔtrxB sulA11R(mcr-73::miniTn10-TetS)2 [dcm] R(zgb-210::Tn10-TetS) endA1 ΔgorΔ(mcrC-mrnr)114::IS10.

Origami B(DE3) is a BL21 derivative that contains mutations in trxB andgor that promote disulfide bond formation in the cytoplasm. The genotypeof Origami B(DE3) is F-ompT hsdSB(rB−mB−) gal dcm lacYI ahpC (DE3)gor522:: Tn10 trxB (KanR, TetR)

Expression screening of these strains was completed as described for E.coli.

Example 14 Expression of Nutritive Polypeptides in B. subtills Bacteria

Gene Synthesis & Plasmid Construction. All of the genes encodingproteins of interest (POI) were cloned by PCR. The templates for PCRamplification of these genes were either synthetic genes, generated forexpression in E. coli (see above), or genomic DNA from a source organism(e.g. B. subtilis). Synthetic genes were codon optimized for expressionin E. coli. All of the genes were cloned with a sequence encoding a1×FLAG tag (a.a.=DYKDDDK) fused, in frame, to their 3′-terminusimmediately preceding the stop codon. For expression in B. subtilis,genes were cloned in the MoBiTec (Göttingen, Germany) expression vector,pHT43, using the Gibson Assembly Master Mix (New England Biolabs,Beverly, Mass.) and the cloning host E. coli Turbo (New England Biolabs)according to manufacturer's instructions. The genes were cloned intopHT43 either as secretion expression constructs (gene fused in-framewith DNA encoding the a-amylase signal peptide (SamyQ) from Bacillusamyloliquefaciens) or as an intracellular expression constructs (geneinserted immediately downstream of the ribosomal binding site (RBS),removing the SamyQ sequence). Following transformation into E. coli,cells containing recombinant plasmids were selected on LB agar platescontaining 100 μg/ml carbenicillin (Cb100). Recombinant plasmids wereisolated from E. coli and their DNA sequences were verified by Sangersequencing prior to transformation into the B. subtilis expression host.

Strain Construction.

B. subtilis strain WB800N was purchased from MoBiTec (Göttingen,Germany) and used as the expression host. WB800N is a derivative of awell-studied strain (B. subtilis 168) and it has been engineered toreduce proteolytic degradation of secreted proteins by deletion of genesencoding 8 extracellular proteases (nprE, aprE, epr, bpr, mpr, nprB, vprand wprA). B. subtilis transformations were performed according to themanufacturer's instructions. Approximately 1 μg of each expressionconstruct was transformed into WB800N and single colonies were selectedat 37° C. by plating on LB agar containing 5.0 μg/ml chloramphenicol(Cm5). Individual transformants were grown in LB broth containing Cm5until they reached log phase. Aliquots of these cultures were mixed withglycerol (20% final concentration) and frozen at −80° C.

Expression Testing.

Frozen glycerol stocks of B. subtilis expression strains were used toinoculate 1-ml of 2×-MAL medium (20 g/l NaC, 20 g/l tryptone, and 10 g/lyeast extract, 75 g/l maltose) with Cm5, in deep well blocks (96-squarewells). Culture blocks were covered with porous adhesive plate seals andincubated overnight in a micro-expression chamber (Glas-Col. TerreHaute, Ind.) at 37° C. and 880 rpm. Overnight cultures were used toinoculate fresh, 2×-MAL, Cm5 cultures, in deep well blocks, to astarting OD600=0.1. These expression cultures were incubated at 37° C.,880 rpm until the OD600=1.0 (approx. 4 hrs) at which time they wereinduced by adding isopropyl-D-1-thiogalactopyranoside (IPTG) at a finalconcentration of 0.1 M and continuing incubation for 4 hrs. After 4 hrs,the cell densities of each culture was measured (OD600) and cells wereharvested by centrifugation (3000 rpm, 10 min, RT). Aftercentrifugation, culture supernatant was carefully removed andtransferred to a new block and cell pellets were frozen at −80° C. Todetermine the levels of secreted protein, 0.5-ml aliquots of the culturesupernatants were filtered first through a 0.45-μm filter followed by a0.22 μm filter. The filtrates were then assayed to determine the levelsof secreted protein of interest (POI).

To determine levels of intracellularly produced POI, frozen cell pelletswere thawed and 0.5 g of 0.1 mm zirconium beads were added to eachsample followed by 0.5 ml of PBS. The cells were lysed in the cold room(4° C.) by bead-beating for 5 min in a Qiagen TissuelyserII (Qiagen,Hilden, Germany) equipped with a 96-well plate adapter. Cell lysateswere centrifuged at 3000 rpm for 10 min and the supernatant was removedand analyzed for POI concentration as described below. To determine thelevels of secreted protein, 0.5-ml aliquots of the culture supernatantswere filtered by a 0.22 μm filter. The filtrates were then assayed todetermine the levels of secreted protein of interest (POI).

Shake Flask Expression.

A single colony was picked from an agar plate for each SEQID andinoculated into 5 mL of 2×Mal media. These shake flasks inocula weregrown in a 30° C. shaker incubator overnight. 5mLs of this overnightculture was used to inoculate 250 mL 2×Mal. Cultures were grown for 4hours at 30° C. then induced for 4 hours at 30° C. Cultures wereharvested by centrifugation. Centrifuged supernatants for each SEQIDwere sterile filtered and frozen at −80° C.

Fermentation Expression.

Soluble protein for SEQID-00105 has been secreted from engineeredBacillus subtilis strains containing episomal or integrated plasmids.The fermentation occurred at a volume of 4 L in a carbon and nitrogenrich media containing Phytone Peptone, Yeast Extract, and Glucose.Fermentation cultures were grown at 30° C., at a pH of 7.0 and a percentdissolved oxygen of 40%. Induction, via the addition of IPTG, occurredat an OD600 nm of 5.0 (+/−1.0). The cultures were supplemented with aGlucose based feed post induction. The cultures were harvested 5-8 hourspost induction. The biomass was then removed via centrifugation and thesupernatant was clarified via filtration and stored at 4° C. untilprocessing.

168 Nutritive Polypeptide Library Gene Synthesis & Plasmid Construction.

For expression in B. subtilis, the vector that was used was derived frompHT43 backbone vector (MoBiTec Göttingen, Germany) with no signalpeptide and grac promoter substituted with aprE promoter and lacIexpression cassette removed. 168 genes encoding for 168 differentprotein sequences that were identified above were made synthetically byLife Technologies/GeneArt as linear fragments (GeneStrings) and selectedfor expression in Escherichia coli. In most cases two genes weresynthesized together in a single linear fragment that had a flanking 5′NdeI restriction site and 3′ BamHI restriction site. All the linearfragments were mixed together at equal molar concentrations. Then thelinear fragments mixture was digested with NdeI and BamHI. The digestedmixtures were cloned into the vector either as secretion expressionconstructs (gene fused in-frame with DNA encoding the lipase signalpeptide (LipAsp) from Bacillus subtilis) or as an intracellularexpression constructs (gene inserted immediately downstream of theribosomal binding site (RBS), with and without N-terminal tag containingMGSHHHHHHH). The library of genes was ligated to the vector PCR productusing T4 DNA ligase (New England Biolabs, Beverly, Mass.). The ligationproducts were transformed into the cloning host, E. coli Turbo (NewEngland Biolabs) according to manufacturer's instructions. 50-100colonies were sequenced to determine the diversity of the leader peptidelibrary. The colonies on the agar plate were then suspended in LB mediaand harvested for plasmid purification.

168 Nutritive Polypeptide Library Strain Construction.

WB800N is a derivative of a well-studied strain (B. subtilis 168) and ithas been engineered to reduce proteolytic degradation of secretedproteins by deletion of genes encoding 8 extracellular proteases (nprE,aprE, epr, bpr, mpr, nprB, vpr and wprA). B. subtilis strain WB800N waspurchased from MoBiTec (Göttingen, Germany) and was modified to have thefollowing mutations WB800N: pXylA-comnK::Erm, degU32(Hy), ΔsigF. Thisnew strain was used as the expression host. Roughly 1 μg of the plasmidmixture purified from E. coli cells was transformed into the expressionstrain. After transformation, 100 μL of the culture were plated ontofour LB 1.5% agar plates containing 5 mg/L chloramphenicol and incubatedat 37° C. for 16 hrs. After incubation, 2 mL of LB media with 5 mg/Lchloramphenicol were added to the surface of each plate containingseveral thousand transformants, and the cells were suspended in thesurface medium by scraping with a cell spreader and mixing. Suspendedcells from the four replicates were pooled together to form thepreinoculum culture for the expression experiment.

168 Nutritive Polypeptide Expression Testing.

The OD600 of the preinoculum culture made from resuspended cells wasmeasured using a plate reader to be roughly 20-25. A 500 mL baffledshake flask containing 50 mL of 2×Mal medium (20 g/L NaCl, 20 g/LTryptone, 10 g/L yeast extract, 75 g/L D-Maltose) with 5 mg/Lchloramphenicol was inoculated to OD600≈0.2 to form the inoculumculture, and incubated at 30° C. shaking at 250 rpm for roughly 6 hours.OD600 was measured and the inoculum culture was used to inoculate theexpression culture in a 2 L baffled shake flask containing 250 ml 2×Malmedium with 5 mg/L chloramphenicol, 1× Teknova Trace Metals, and 0.01%Antifoam 204 to an OD600 of 0.1. The culture was shaken for 30° C. and250 rpm for 18 hours, at which point the culture was harvested. For thesecreted protein library constructs, the terminal cell density wasmeasured and the supernatant was harvested by centrifugation (5000×g, 30min, RT) and filtered using 0.22 um filter. For the intracellularprotein library constructs, the terminal cell density was measured andthe cells were harvested by centrifugation (5000×g, 30 min, RT). Cellswere then lysed using microfluidizer and the soluble fraction waspurified using nickel affinity column if the construct library hadN-terminal His tag. Otherwise the soluble fraction was used for furtheranalysis. All the samples were run on SDS-PAGE gels, separated into tenfractions, and then analyzed using LC-MS/MS as described below. 40/168proteins were successfully secreted, 10/168 proteins were successfullyproduced intracellularly without His tag and 28/168 proteins weresuccessfully produced intracellularly with 5′ 8×His tag in Bacillussubtilis. Based on the results, certain genes were individually clonedand tested for individual secretion in Bacillus subtilis.

Secreted Nutritive Polypeptide Plasmid Construction.

For this study, the pHT43 backbone vector with no signal peptide wasmodified by removing the SamyQ signal peptide to allow for the nativesignal peptide to guide secretion, substituting the grac promoter withthe aprE promoter, removing the lacI region, and adding a 1×FLAG tag(DYKDDDDK) before the terminator region. The unmodified pHT43 vectorfrom MoBiTec contains the Pgrac promoter, the SamyQ signal peptide, Ampand Cm resistance genes, a lacI region, a repA region, and the ColE1origin of replication. To amplify the genes of interest, genomic DNApreps were made from wild-type Bacillus strains. Secreted nutritivepolypeptide genes including their native signal peptide coding regionswere PCR amplified using PCR primers with tails containing 25 bphomology regions to the pHT43 backbone and were run on a 1% Agarose TAEgel to check for correct insert size. 10 μL from each PCR were pooledtogether into a single library of inserts, and the mix was Gibsonligated to a pHT43 backbone vector. The ligation was transformed into10-Beta electrocompetent cells (New England Biolabs), and transformedcells were plated at a 10-1 dilution onto four LB agar plates with 100mg/L carbenicillin. One plate was sequenced using a forward primer thatbinds in the promoter region and a reverse primer that binds in theterminator region. 2 mL of LB medium with 100 mg/L carbenicillin wasadded to the remaining three plates. Cells were scraped and suspendedinto the LB medium, and the plasmids were extracted from the cellsuspensions to form the multiplex plasmid mix to be transformed into theexpression strain. The secreted polypeptide library strain constructionand expression were done similar to 168 nutritive polypeptide librarystrain construction and expression testing.

Secretion Leader Peptide Library Construction.

Secretion signal peptide libraries facilitate the secretion of any givenprotein of interest. One approach to enhancing secretion is to fuse alibrary of signal peptide sequences to the protein of interest andscreen for those that result in the highest level of secretion. Thesignal peptide library described here consists of 173 signal peptidesthat were identified as being associated to naturally Sec mediatedsecreted proteins in Bacillus subtilis (Brockmeier et al MolecularBiology, 2006). A signal peptide library was generated for SEQID-43136,starting with plasmid pES1207 which has SEQID-43136 fused to the signalpeptide from the B. amyloliquefaciens α-amylase (SamyQ), pES1207 wasused as template for a PCR reaction with primers, Pfwd and Prev, whichamplified the entire plasmid except for the SamyQ sequence. Pfwd andPrev possessed tails that had AarI restriction sites and the PCRproducts were purified and cut with Aar I. The fragment was thendephosphorylated using Antarctic phosphatase (New England Biolabs,Beverly, Mass.). DNA encoding the individual signal peptides wasconstructed by duplexing single stranded oligonucleotides comprising theforward- and reverse-strands of each signal peptide sequence. Theoligonucleotides were designed such that single strand tails were formedat the 5′-ends of the duplexed molecule. These were complementary of theoverhangs generated by the AarI digestion of the vector PCR fragment. Toduplex the oligonucleotides, the direct strand and the reverse strandoligonucleotides were mixed together, phosphorylated using T4polynucleotide kinase (New England Biolabs, Beverly, Mass.) andannealed. Post annealing, signal peptide DNA sequences were mixed inequal proportion in a single tube. The library of signal peptides wasligated to the vector PCR product using T4 DNA ligase (New EnglandBiolabs, Beverly, Mass.). The ligation products were transformed intothe cloning host, E. coli Turbo (New England Biolabs) according tomanufacturer's instructions. 50-100 colonies were sequenced to determinethe diversity of the leader peptide library for SEQID-00298 andSEQID-00338. The colonies on the agar plate were then suspended in LBmedia and harvested for plasmid purification.

Secretion Leader Peptide Library Strain Construction.

B. subtilis strain WB800N (MoBiTec, (Göttingen, Germany) was used as theexpression host. Approximately 10 μg of signal peptide library of aparticular protein construct was transformed into WB800N and singlecolonies were selected at 37° C. by plating on LB agar containing 5.0μg/ml chloramphenicol (Cm5). The leader peptide library screening forSEQID-00105, SEQID-00352, SEQID-00341, SEQID-00103 were carried out inB. subtilis WB800N that has been modified to have mutations in the sigFsporulation factor and also the intracellular serine protease (ispA) wasdisrupted with an antibiotic marker. The strain also had an induciblecomK (the competence initiation transcription factor) integrated intochromosome for higher transformation efficiency.

Secretion Leader Peptide Library Expression Screening.

400-500 individual transformants of the B. subtilis signal peptidelibrary were used to inoculate individual, 1-ml cultures of 2×-MALmedium (20 g/l NaCl, 20 g/l tryptone, and 10 g/l yeast extract, 75 g/lmaltose) with Cm5, in deep well blocks (96-square wells). In addition tothe signal peptide library strains, a strain containing plasmid with theprotein of interest and the SamyQ leader peptide was inoculated as acontrol. Culture blocks were covered with porous adhesive plate sealsand incubated overnight in a micro-expression chamber (Glas-Col, TerreHaute, Ind.) at 37° C. and 800 rpm. Overnight cultures were used toinoculate fresh, 2×-MAL, Cm5 cultures, in deep well blocks, to astarting OD600=0.15,

Expression cultures were incubated at 37° C., 880 rpm until theOD600=1.0 (approx. 4 hrs) at which time they were induced by addingisopropyl β-1-thiogalactopyranoside (IPTG) at a final concentration of 1mM and continuing incubation for 4 hrs. After 4 hrs, the cell densitiesof each culture was measured (OD600) and cells were harvested bycentrifugation (3000 rpm, 10 min, RT). After centrifugation, the culturesupernatant was carefully removed and transferred to a new block andcell pellets were frozen at −80° C. To determine the levels of secretedprotein, 0.5-ml aliquots of the culture supernatants were filtered firstthrough a 0.45-μm filter followed by a 0.22 μm filter. The filtrateswere then assayed by Chip electrophoresis, as described herein, todetermine the levels of secreted protein of interest (POI) and comparedwith the level of secretion of base construct.

Diluted overnight cultures were used as inoculum for LB broth culturescontaining Cm5. These cultures were grown at 37 C until they reached logphase. Aliquots of these cultures were mixed with glycerol (20% finalconcentration) and frozen at −80° C. The top 10-15 hits were thenpurified using Instagene matrix (Biorad, USA) and amplified around thesignal peptide and sent for sequencing to identify the signal peptidesequence.

TABLE E14AExemplary results of B. subtilis leader peptide library screening.SEQID- SEQID- SEQID- SEQID- SEQID- SEQID- Other Gene 298 00338 0010500352 00341 00103 SEQ IDs SEQID Name Protein Sequence mg/l/OD mg/l/ODmg/l/OD mg/l/OD mg/l/OD mg/l/OD mg/l/OD 3921 abnA MKKKKTWKRFLHFSSA 4.49.4 135.7 ~ 148.14 12.1 3.1 ALAAGLIFTSAAPAEA SEQID- 00405 3922 bglCMKRSISIFITCLLITL 7.8 ~ 73.6 2.7 33.9 12.1 ~ LTMGGMIASPASA 3923 bprMRKKKTKNRLISSVLS ~ ~ ~ ~ 40.4 ~ ~ TVVISSLLFPGAAGA 3924 glpQMRKNRILALFVLSLGL ~ 5.7 ~ ~ 41.9 ~ 5.5 LSFMVTPVSA SEQID- 00398 3925 lipAMKFVKRRIIALVTILM 14.1 ~ ~ 10.9 ~ 16.1 ~ LSVTSLFALQPSAKAA 3926 lytBMKSCKQLIVCSLAAIL ~ 3.4 ~ ~ ~ ~ ~ LLIPSVSFA 3927 lytF MKKKLAAGLTASAIVG ~~ ~ ~ ~ 14.8 ~ TTLVVTPAEA 3928 mpr MKLVPRFRKQWFAYLT 10.8 ~ ~ ~ ~ ~ ~VLCLALAAAVSFGVPA KA 3929 nprB MRNLTKTSLLLAGLCT ~ ~ ~ ~ 37.5 ~ ~AAQMVFVTHASA 3930 pelB MKRLCLWFTVFSLFLV ~ ~ ~ ~ 64.4 ~ ~ LLPGKALG 3931penP MKLKTKASIKFGICVG ~ ~ ~ 2.8 ~ ~ ~ LLCLSITGFTPFFNST HAEA 3932 phoBMKKFPKKLLPIAVLSS 7.9 ~ ~ ~ ~ ~ ~ IAFSSLASGSVPEASA 3933 wapAMKKRKRRNFKRFIAAF ~ 7 ~ 2.14 ~ ~ ~ LVLALMISLVPADVLA 3934 xynAMFKPKKNFLVGLSAAL 4.3 8.8 114.4 ~ 83.3 13.4 ~ MSISLFSATASA 3935 ybfOMKRMIVRMTLPLLIVC ~ ~ ~ 0.69 ~ ~ ~ LAFSSFSASARA 3936 yekDMKRITINIITMFIAAA ~ ~ ~ ~ 61.7 ~ ~ VISLTGTAEA 3937 yddT MRKKRVITCVMAASLT~ ~ 135.6 ~ ~ ~ ~ LGSLLPAGYASA 3938 yfhK MKKKQVMLALTAAAGL ~ ~ ~ ~ ~ 20.8~ GLTALHSAPAAKA 3939 yfjS MKWMCSICCAAVLLAG ~ ~ ~ ~ ~ 9.4 ~ GAAQA 3940yjeM MKKELLASLVLCLSLS ~ ~ 83.4 ~ 80.2 ~ ~ PLVSTNEVFA 3941 yjdBMNFKKTVVSALSISAL ~ ~ 152.7 ~ ~ 14.3 ~ ALSVSGVASA 3942 yjfAMKRLFMKASLVLFAVV ~ ~ ~ ~ ~ 20 ~ FVFAVKGAPAKA 3943 ykoJ MLKKKWMVGLLAGCLA~ ~ ~ 2.23 132.5 ~ ~ AGGFSYNAFA 3944 ylqB MKKIGLLFMLCLAALF ~ ~ ~ ~ ~13.3 ~ TIGFPAQQADA 3945 yndA MRFTKVVGFLSVLGLA ~ ~ 124.3 ~ ~ ~ ~AVFPLTAQA 3946 yqgA MKQGKFSVFLILLLML 3.9 ~ ~ ~ ~ ~ ~ TLVVAPKGKAEA 3947yraI MTLTKLKMLSMLTVMI ~ 6.3 ~ ~ ~ ~ ~ ASLFIFSSQALA 3948 yuaBMKRKLLSSLAISALSL ~ ~ ~ ~ ~ ~ 2.5 GLLVSAPTASFAAE SEQID- 00404 3949 yurIMTKKAWFLPLVCVLLI ~ ~ ~ 2.26 ~ ~ ~ SGWLAPAASASA 3950 yveEMRKSLITLGLASVIGT ~ ~ 124.4 ~ ~ 14.6 ~ SSFLIPFTSKTASA 3951 yvgOMKRIRIPMTLALGAAL ~ ~ ~ ~ ~ 17.7 ~ TLAPLSFASA 3952 yvnB MRKYTVIASILLSFLS~ ~ ~ ~ ~ 26.2 ~ VLSGG 3953 ywaD MKKLLTVMTMAVLTAG ~ ~ ~ ~ ~ ~ 3.4TLLLPAQSVTPAAHA SEQID- 403 3954 ywaB MMNKPTKLFSTLALAA ~ ~ 13.1 ~ ~ ~ ~GMTAAAAGGAGTIHA 3955 yxaK MVKSFRMKALIAGAAV ~ ~ ~ 3.7 ~ ~ ~AAAVSAGAVSDVPAAK VLQPTAAYA 3956 yxiT MKWNNMLKAAGIAVLL ~ 7.9 ~ 0.95 41.5~ ~ FSVFAYAAPSLKAVQA

Example 15 Expression of Nutritive Polypeptides in Aspergillus nigerFungi

Gene Synthesis & Plasmid Construction.

Genes encoding natively secreted proteins were PCR amplified from theAspergillus niger ATCC 64974 using primers designed from the genomesequence of Aspergillus niger CBS 513.88. In one example, genes includednative 5′ secretion sequences and were cloned into the expression vectorpAN56-1 (Genbank: Z32700.1) directly under the control of the gpdApromoter from Aspergillus nidulans with the addition of a C-terminal3×FLAG tag (DYKDHDGDYKDHDIDYKDDDDK). In another example genes includedonly the mature peptide with the addition of a heterologous 5′ secretionsignal. Plasmids were constructed using the Gibson Assembly Kit (NewEngland Biolabs, Beverly, Mass.). Recombinant plasmids were sequenceverified before transformation into Aspergillus hosts.

pFGLAHIL6T was obtained from the BCCM/LMBP (Ghent, Netherlands).Plasmids were constructed using the Gibson Assembly Kit (New EnglandBiolabs, Beverly, Mass.). Recombinant plasmids were sequence verifiedbefore transformation into Aspergillus hosts.

The pyrA nutritional marker was PCR amplified from Aspergillus nigerATCC 64974 using primers designed from genome sequence of Aspergillusniger ATCC 1015. The pyrA PCR fragment was digested with XbaI andligated into an XbaI fragment of pCSN44 (Staben et al., 1989) toconstruct pES1947, pCSN44 was obtained from the BCCM/LMBP (Ghent,Netherlands). The recombinant plasmid was sequence verified beforetransformation into Aspergillus hosts.

Strain Construction. A protease deficient derivate of Aspergillus nigerATCC 62590 was used as the expression host. Expression vectors wereco-transformed with pES1947 using the protoplast method as described inPunt et al., 1992, Methods in Enzymology, 216, 447-457. Approximately 5ug of each plasmid was transformed into Aspergillus niger protoplasts.Transformants were selected on minimal media supplemented with 1.2 Msorbitol and 1.5% bacto agar (10 g/f glucose, 4 g/l sodium nitrate, 20mg/l salts solution (containing 26.2 g/l potassium chloride and 74.8 g/lPotassium phosphate monobasic at pH 5.5), 1 ml/l vitamin solution(containing 100 mg/l Pyridoxine hydrochloride, 150 mg/l Thiaminehydrochloride, 750 mg/l 4-Aminobenzoic acid, 2.5 g/l Nicotinic acid, 2.5g/l riboflavin, 20 g/l choline chloride, and 30 mg/l biotin), and 1 ml/1of metals solution (containing 20 g/l Zinc sulfate heptahydrate(ZnSO4-7H2O), 11 g/l Boric acid (H3BO3), 5 g/l Manganese (II) chloridetetrahydrate (MnCl2-4H2O), 5 g/l Iron (II) sulfate heptahydrate(FeSO4-7H2O). 1.7 g/l Cobalt(II) chloride hexahydrate (CoCl2-6H2O), 1.6g/l Copper(II) sulfate pentahydrate (CuSO4-5H2O), 1.5 g/l Sodiummolybdate dihydrate (NaMoO4-2H2O), and 5.0 g/l EDTA disodium saltdihydrate (Na2EDTA-2H2O) at pH 6.5). Individual transformants wereisolated on minimal media plates and allowed to grow at 30 C until theysporulated. Spores were harvested in water and stored at 4 C.

Expression Testing.

Spore stocks of Aspergillus niger strains were inoculated at 10⁶spores/ml into 2 mL of CM (MM plus 5.0 g/l yeast extract, 2.0 g/lcasamino acids) adjusted to pH 7 with 40 mM MES and SigmaFast ProteaseInhibitor Cocktail (1 tab/100 mL, Sigma Aldrich) in 24 well squarebottom deep well blocks. Culture blocks were covered with porousadhesive plate seals and incubated for 48 hrs in a micro-expressionchamber (Glas-Col, Terre Haute, Ind.) at 30° C. at 600 rpm. After thegrowth period, 0.5-ml aliquots of the culture supernatants were filteredfirst through a 25 μm/0.45-μm dual stage filter followed by a 0.22 μmfilter. The filtrates were then assayed to determine the levels ofsecreted protein of interest (POI).

TABLE E15AExemplary results of Aspergillus leader peptide library screening.signal peptide name (gene name_species SEQID name) signal sequenceGenotype 3957 native signal MRWLLTSSALLVPAAAPgpdA-native signal peptide-SEQID-00409-3XFlag peptide 3958 AXHA_ASPNGMKFLKAKGSLLSSGIYLIALAPFVNA PgpdA-AXHA_ASPNG-SEQID-00409-3XFlag 3959PPIB_ASPNG MNFKNIFLSFFFVLAVGLALVHA PgpdA-PPIB_ASPNG-SEQID-00409-3XFlag3960 FAEA_ASPNG MKQFSAKYALILLATAGQALAPgpdA-FAEA_ASPNG-SEQID-00409-3XFlag 3961 BGAL_ASPNG MKLSSACAIALLAAQAAGAPgpdA-BGAL_ASPNG-SEQID-00409-3XFlag 3962 PLYA_ASPNG MKYSTIFSAAAAVFAGSAAAPgpdA-PLYA_ASPNG-SEQID-00409-3XFlag 3963 PRTA_ASPNG MKFSTILTGSLFATAALAPgpdA-PRTA_ASPNG-SEQID-00409-3XFlag 3964 AGALC_ASPNGMIGSSHAVVALGLFTLYGHSAA PgpdA-AGALC_ASPNG-SEQID-00409-3XFlag 3965PHYB_ASPNG MPRTSLLTLACALATGASA PgpdA-PHYB_ASPNG-SEQID-00409-3XFlag 3966AORSN_ASPOR MRPLSHLSFFNGLLLGLSALSA PgpdA-AORSN_ASPOR-SEQID-00409-3XFlag3967 DPP5_ASPOR MGALRWLSIAATASTALA PgpdA-DPP5_ASPOR-SEQID-00409-3XFlag3968 PHYA_ASPNG MGVSAVLLPLYLLSGVTSGLAVPPgpdA-PHYA_ASPNG-SEQID-00409-3XFlag 3969 EXG_ASPOR MLPLLLCIVPYCWSPgpdA-EXG_ASPOR-SEQID-00409-3XFlag 3970 native signal MHFLQNAVVAATMGAALAPgpdA-native signal peptide-SEQID-00420-3XFlag peptide 3971 PPA1_ASPNGMKGTAASALLIALSATAAQA PgpdA-PPA1_ASPNG-SEQID-00420-3XFlag 3972 PEPC_ASPNGMKGILGLSLLPLLTAA PgpdA-PEPC_ASPNG-SEQID-00420-3XFlag 3973 PRTA_ASPNGMKFSTILTGSLFATAALA PgpdA-PRTA_ASPNG-SEQID-00420-3XFlag 3974 AGALC_ASPNGMIGSSHAVVALGLFTLYGHSAA PgpdA-AGALC_ASPNG-SEQID-00420-3XFlag 3975RNT1_ASPOR MMYSKLLTLTTLLLPTALALPSLVERPgpdA-RNT1_ASPOR-SEQID-00420-3XFlag 3976 PGLR1_ASPNG MHSYQLLGLAAVGSLVSAPgpdA-PGLR1_ASPNG-SEQID-00420-3XFlag 3977 ORYZ_ASPORMQSIKRTLLLLGAILPAVLGA PgpdA-ORYZ_ASPOR-SEQID-00420-3XFlag 3978PLYB_ASPNG MHYKLLFAAAAASLASAVSA PgpdA-PLYB_ASPNG-SEQID-00420-3XFlag 3979NUS1_ASPOR MPRLLPISAATLALAQLTYG PgpdA-NUS1_ASPOR-SEQID-00420-3XFlag 3980PHYB_ASPNG MPRTSLLTLACALATGASA PgpdA-PHYB_ASPNG-SEQID-00420-3XFlag 3981TAN_ASPOR MRQHSRMAVAALAAGANA PgpdA-TAN_ASPOR-SEQID-00420-3XFlag 3982PDI_ASPNG MRSFAPWLVSLLGASAVVAA PgpdA-PDI_ASPNG-SEQID-00420-3XFlag 3983XYN2_ASPNG MLTKNLLLCFAAAKAALA PgpdA-XYN2_ASPNG-SEQID-00420-3XFlag 3984PHYA_ASPOR MAVLSVLLPITFLLSSVTG PgpdA-PHYA_ASPOR-SEQID-00420-3XFlag 3985DPP5_ASPOR MGALRWLSIAATASTALA PgpdA-DPP5_ASPOR-SEQID-00420-3XFlag 3986PHYA_ASPNG MGVSAVLLPLYLLSGVTSGLAVP PgpdA-PHYA_ASPNG-SEQID-00420-3XFlag3987 PEPA_ASPNG MVVFSKTAALVLGLSTAVSA PgpdA-PEPA_ASPNG-SEQID-00420-3XFlag3988 AGLU_ASPNG MVKLTHLLARAWLVPLAYGASQSLLPgpdA-AGLU_ASPNG-SEQID-00420-3XFlag 3989 ABFA_ASPNGMVAFSALSGVSAVSLLLSLVQNAHG PgpdA-ABFA_ASPNG-SEQID-00420-3XFlag 3990AMYG_ASPNG MSFRSLLALSGLVCTGLA PgpdA-AMYG_ASPNG-SEQID-00420-3XFlag 3991PHOA_ASPNG MFTKQSLVTLLGGLSLAVA PgpdA-PHOA_ASPNG-SEQID-00420-3XFlag 3992ABFB_ASPNG MFSRRNLVALGLAATVSA PgpdA-ABFB_ASPNG-SEQID-00420-3XFlag

Aspergillus niger Signal Peptide Library Construction.

It is difficult to predict which secretion signal peptide willfacilitate the secretion of any given protein of interest best.Therefore, one approach to optimizing secretion is to fuse a library ofsignal peptide sequences to the protein and screen for those that resultin the highest level of secretion. We constructed a signal peptidelibrary for SEQID-00409 and SEQID-00420. Table E15A shows the signalpeptides that were used with SEQID-00409 and SEQID-00420. DNA encodingthe individual signal peptides was constructed by duplexing singlestranded oligonucleotides comprising the forward- and reverse-strands ofeach signal peptide sequence. The oligonucleotides were designed suchthat single strand tails were formed at the 5′-ends of the duplexedmolecule. Genes encoding natively secreted proteins SEQID-00409 andSEQID-00420 were PCR amplified from the Aspergillus niger ATCC 64974using primers designed from the genome sequence of Aspergillus niger CBS513.88. Genes included native 5′ secretion sequences and were clonedinto the expression vector pAN56-1 (Genbank: Z32700.1) directly underthe control of the gpdA promoter from Aspergillus nidulans with theaddition of a C-terminal 3×FLAG tag (DYKDHDGDYKDHDIDYKDDDDK). Then thevectors were amplified without the native signal peptide and plasmidswith different signal peptides were reconstructed with the duplex signalpeptide sequences using the Gibson Assembly Kit (New England Biolabs,Beverly, Mass.). Recombinant plasmids were sequence verified beforetransformation into Aspergillus hosts.

The pyrA nutritional marker was PCR amplified from Aspergillus nigerATCC 64974 using primers designed from genome sequence of Aspergillusniger ATCC 1015. The pyrA PCR fragment was digested with XbaI andligated into an XbaI fragment of pCSN44 (Staben et al., 1989) toconstruct pES1947, pCSN44 was obtained from the BCCM/LMBP (Ghent,Netherlands). The recombinant plasmid was sequence verified beforetransformation into Aspergillus hosts.

Aspergillus niger Signal Peptide Library Strain Construction.

A protease deficient derivate of Aspergillus niger ATCC 62590 was usedas the expression host. Each signal peptide-gene combination vector wasindividually co-transformed with plasmid containing the nutritionalmarker pyrG using the protoplast method as described in Punt et al.,1992. Approximately 5 ug of each plasmid were transformed intoAspergillus niger protoplasts. Transformants were selected on minimalmedia supplemented with 1.2 M sorbitol and 1.5% bacto agar (10 g/lglucose, 4 g/l sodium nitrate, 20 ml/l salts solution (containing 26.2g/l potassium chloride and 74.8 g/l Potassium phosphate monobasic at pH5.5), 1 ml/l vitamin solution (containing 100 mg/l Pyridoxinehydrochloride, 150 mg/l Thiamine hydrochloride, 750 mg/l 4-Aminobenzoicacid, 2.5 g/l Nicotinic acid, 2.5 g/l riboflavin, 20 g/l cholinechloride, and 30 mg/l biotin), and 1 ml/l of metals solution (containing20 g/l Zinc sulfate heptahydrate (ZnSO4-7H2O), 11 g/l Boric acid(H3B03), 5 g/l Manganese (II) chloride tetrahydrate (MnCl2-4H2O), 5 g/lIron (II) sulfate heptahydrate (FeSO4-7H2O), 1.7 g/l Cobalt(II) chloridehexahydrate (CoCl2-6H2O), 1.6 g/l Copper(II) sulfate pentahydrate(CuSO4-5H2O), 1.5 g/l Sodium molybdate dihydrate (NaMo 4-2H2O), and 5.0g/l EDTA disodium salt dihydrate (Na2EDTA-2H2O) at pH 6.5). Individualtransformants were isolated on minimal media plates and allowed to growat 30 C until they sporulated.

Aspergillus niger Signal Peptide Library Expression Testing.

Six different primary transformants from each construct were inoculatedinto 1 ml of minimal media as defined above supplemented with 5.0 g/lyeast extract 2.0 g/l casamino acids) adjusted to pH 7 with 160 mM MESin 96 deep well culture blocks. Culture blocks were covered with porousadhesive plate seals and incubated for 48 hrs in a micro-expressionchamber (Glas-Col, Terre Haute, Ind.) at 33° C. at 800 rpm. After thegrowth period, 0.5-ml aliquots of the culture supernatants were filteredfirst through a 25 μm/0.45-μm dual stage filter followed by a 0.22 μminfilter. The filtered supernatants were then analyzed using ChipElectrophoresis as described below or anti-FLAG DOT-BLOT and SDS-PAGE asdescribed below. Based on these results the primary transformants, whichdemonstrated higher secretion than the native signal peptide, wereisolated on minimal media plate and allowed to grow at 30° C. until theysporulated.

Spore stocks of the above Aspergillus niger strains along with thecontrol Aspergillus niger strain that contain expression construct ofpgpdA promoter and native signal peptide of SEQID-00409 and SEQID-00424were inoculated at 10⁶ spores/mL into 10 mL of minimal media as definedabove supplemented with 5.0 g/l yeast extract, 2.0 g/l casamino acids)adjusted to pH 7 with 160 mM MES in 125 ml plastic flask. Aspergillusspores were then grown at 30° C. with 150 RPM for two days. After thegrowth period, aliquots of the culture supernatants were filtered firstthrough a 25 m/0.45-μm dual stage filter followed by a 0.22 μm filter.The filtrates were then analyzed using SDS-PAGE as described herein.

FIG. 5, demonstrates the secretion of SEQID-00409 (left) and SEQID-00420(right) with new signal peptide compared to native signal peptide.

Aspergillus niger Heterologous Nutritive Polypeptide Gene Synthesis &Plasmid Construction.

Genes encoding nutritive polypeptides were synthesized (Geneart, LifeTechnologies). Genes were codon optimized for expression in Aspergillusniger. Synthesized genes were PCR amplified and cloned into theexpression vector pAN56-1 (Genbank: Z32700.1) fused to glucoamylase withits native leader sequence under the control of the gpdA promoter fromAspergillus nidulans with the addition of a C-terminal 3×FLAG tag(DYKDHDGDYKDHDIDYKDDDDK) and Kexin protease site (NVISKR) betweenglucoamylase gene and gene of interest. Plasmids were constructed usingthe Gibson Assembly Kit (New England Biolabs, Beverly, Mass.).Recombinant plasmids were sequence verified before transformation intoAspergillus hosts.

SEQID-00087, SEQID-00103, SEQID-00105, SEQID-00115, SEQID-00218,SEQID-00298, SEQID-00302, SEQID-00341, SEQID-00352, SEQID-00354 geneswere utilized.

Aspergillus niger Heterologous Nutritive Polypeptide StrainConstruction.

A protease deficient derivate of Aspergillus niger D15#26 (E.Karnaukhova et al, Microbial Cell Factories, 6:34) was used as theexpression host. 10 ug of Expression vectors were co-transformed withlug plasmid containing pyrG selection marker using the protoplast methoddescribed in Punt et al., 1992, Methods in Enzymology, 216, 447-457.Transformants were selected on minimal media containing 10 g/l glucose,6 g/l sodium nitrate, 20 ml/l salts solution (containing 26 g/lpotassium chloride and 76 g/l Potassium phosphate monobasic at pH 5.5),2 mM magnesium sulphate, 1 ml/l vitamin solution (containing 100 mg/lPyridoxine hydrochloride, 150 mg/l Thiamine hydrochloride, 750 mg/l4-Aminobenzoic acid, 2.5 g/l Nicotinic acid, 2.5 g/l riboflavin, 20 g/lcholine chloride, and 30 mg/I biotin), and 1 ml/l of metals solution(containing 20 g/l Zinc sulfate heptahydrate (ZnSO4-7H2O), 11 g/l Boricacid (H3B03), 5 g/l Manganese (II) chloride tetrahydrate (MnCl2-4H2O), 5g/l Iron (II) sulfate heptahydrate (FeSO4-7H2O), 1.7 g/l Cobalt(II)chloride hexahydrate (CoCl2-6H2O), 1.6 g/l Copper(II) sulfatepentahydrate (CuSO4-5H2O), 1.5 g/l Sodium molybdate dihydrate(NaMoO4-2H2O), and 5.0 g/l EDTA disodium salt dihydrate (Na2EDTA-2H2O)at pH 6.5) and supplemented with 1.2 M sorbitol and 1.5% bacto agar.Individual transformants were isolated on minimal media plates andallowed to grow at 30 C until they sporulated. Spores were harvested inwater at stored at 4 C.

Aspergillus niger Heterologous Nutritive Polypeptide Expression Testing.

90 different primary transformants from each construct were inoculatedinto 1 ml of minimal media as defined above supplemented with 1 g/Lcasamino acids in 96 deep well culture blocks (1^(st) MTP). Cultureblocks were covered with porous adhesive plate seals and incubated for72 hrs in a micro-expression chamber (Glas-Col, Terre Haute, Ind.) at33° C. at 800 rpm. After the growth period, 0.5-ml aliquots of theculture supernatants were filtered first through a 25 μm/0.45-μm dualstage filter followed by a 0.22 μm filter. The filtrates were thenassayed using an anti-FLAG ELISA method, as described herein, todetermine the levels of secreted protein of interest (POI). At leastfive colonies from nine expression constructs excluding SEQID-00302yielded positive signals in an anti-flag ELISA as reported in Table E15B. At least 5 primary transformants that showed positive signals inanti-FLAG ELISA assay from each of the nine expression strains were alsostreaked onto a fresh minimal media agar plate for single sporepurification and retested for confirmation (2^(nd) MTP).

Spores were harvested from the plate and inoculation was done with freshspore crops with a density of approximately 1E9 spores/ml. 10 ul ofthese spore crops were added to 10 ml of minimal medium giving a startdensity of 1E6 spores/ml. Aspergillus spores were then grown at 33 Cwith 150 RPM for three days. After the growth period, aliquots of theculture supernatants were filtered first through a 25 μm/0.45-μm dualstage filter followed by a 0.22 μm filter. The filtrates were thenanalyzed using anti-FLAG ELISA, anti-flag western blot and SDS-PAGEdescribed below.

Certain clones from different expression construct were grown usingfresh spore crops with a final density of approximately, 1E6 spores/mlin one litre minimal media. Aspergillus spores were then grown at 33 Cwith 150 RPM for three days. After the growth period, aliquots of theculture supernatants were filtered first through a 25 μm/0.45-μm dualstage filter followed by a 0.22 μm filter. The filtrates were thenanalyzed using anti-FLAG ELISA, anti-flag western blot and SDS-PAGEdescribed below. Any secreted protein above 39 mg/l in an anti-flagELISA from a one liter shake flask were detected by an anti-FLAG westernblot and SDS-PAGE.

TABLE E15B demonstrates the anti-flag ELISA results and anti-FLAGwestern blot results of different protein secretion in Aspergillus nigerELISA ELISA ELISA ELISA 10 ml Western 1 litre 1st MTP 2nd MTP shakeflask 10 ml shake flask SEQ ID # (mg/l) (mg/l) (mg/l) shake flask (mg/l)SEQID-00103 14.7-42.2  3.0-29.1 1.6-4.0 ++ 1.2-5.6 SEQID-00105  1.4-20.2  0-2.1   0-2.4 + 0.2-1.6 SEQID-00298  66.0-215.4  5.2-119.5  1.3-79.4+++  93.9-224.3 SEQID-00897 11.9-21.4  3.6-17.5 0.6-2.2 + − SEQID-0011516.3-96.2   0-4.9 0.7-3.7 − − SEQID-00218 28.2-69.3  0.4-191.7 2.1-13.3 + − SEQID-00341 10.4-25.3  1.9-20.5 3.0-8.3 +++ 1.0-3.6SEQID-00352  27.1-207.6   0-16.2   0.7-245.70 +++  39.0-124.3SEQID-00354  9.1-120.4   0-47.2 0.9-7.8 +++   0-1.2

Example 16 Expression of Nutritive Polypeptides in Cultured MammalianCells

Gene Synthesis and Plasmid Construction.

All genes were made synthetically (GeneArt, Life Technologies) andoptimized for expression in Homo Sapiens. Genes encoding SEQID-0001,SEQID-00103, SEQID-00105, SEQID-00298 and SEQID-00363 were chosen forsecretion in mammalian cells. All the genes were fused with 5′ signalpeptide sequence from 1 g-kappa protein (METDTLLLWVLLLWVPGSTGD) andHHHHHHHH tag in the 3′ end. All the gene constructs were cloned to pcDNA3.1 (+) vector (Life Technologies) downstream of pCMV promoter in themultiple cloning site of NheI and BamHI. All gene sequences containedthe GCC sequence upstream of start codon to generate GCCATGG Kozaksequence. All plasmids were transformed in E. coli, sequence verifiedand 10 mg of each plasmid were purified for transfection into mammaliancells.

Strain Construction.

The cell lines selected for experimentation are 2 transient lines fromInvitrogen, FreeStyle™ CHO-S Cells (PN 51-4448) and FreeStyle™ 293FCells (PN 51-0029). Cell lines were received from Invitrogen and storedin liquid nitrogen until sub-culturing was initiated. For sub-culturingprior to transfection, cells were thawed into specific media: CHO-Scells were thawed into 30 mL of FreeStyle™ CHO Expression Media(Invitrogen PN 12651-014) supplemented with 8 mM Glutamax (Invitrogen PN35050-061) and 1× HT (Invitrogen PN 11067-030). 293F cells were thawedinto 30 mL FreeStyle™ 293 Expression Medium (Invitrogen PN 12338-018).Cells were allowed to recover in suspension for 72 hrs under 80%humidity, 8% Carbon Dioxide, 36.5° C., shaking at 110 rotations perminute. Cells were passed from viable cell densities (VCD) not exceeding2.0×10 6 cells/mL to 0.2×10 6 cells/mL. Sub-culturing continued for 5passages prior to transfection.

At 26 hrs prior to transfection the cultures were passed back to 0.6×106 viable cells/mL in a volume of 60 mL. Each nutritive polypeptide wastransfected in duplicate with 2 mock transfections performed as controlfor each cell line. On the day of transfection cells were counted anddetermined to be at 1.1×10 6 cells/mL with greater than 98% viability.

Transfection Procedure.

Preparation of DNA-lipid complexes for 120 mL total volume (60 mL/250 mLshake flask) transfections.

The following procedure was performed in a Laminar Flow Hood. 150 μg ofplasmid DNA were diluted into OptiPRO™ SFM Reduced Serum Medium(Invitrogen PN: 12307-050 to a total volume of 2.4 mL. This solution wasmixed gently and 0.2 μm filter sterilized. Diluted 150 uL of FreeStyle™MAX Reagent (Invitrogen PN 16447-100) in OptiPRO™ SFM Reduced SerumMedium to a total volume of 2.4 mL, mixed gently and incubated for 5minutes at room temperature. After 5-minute incubation, the 2.4 mL ofdiluted DNA was added to the 2.4 mL of the diluted reagent, gently mixedand incubated for 20 min at room temperature to form the DNA-lipidcomplex. After 20-minute incubation, 2.4 mL of complex was added to eachduplicate flask. Control Flask received 2.4 mL of OptiPRO™ SFM reducedserum medium. Transfected flasks were placed back in incubated shakerunder 80% humidity, 8% Carbon Dioxide 36.5° C., shaking at 110 rotationsper minute. Cultures were monitored for % Viability and VCD. All flaskswere supplemented on Day 3 with a 20% Phytone Peptone Feed made in themedia specific to each cell line. The final concentration of PhytonePeptone in the flask equaled 2%. Cultures were harvested on Day 4 viacentrifugation and 0.2 um filtration of the supernatant. Supernatantswere run on a non-reducing SDS-PAGE 12% Bis-Tris Gel to confirmexpression of nutritive polypeptides at molecular weights. SEQID-00001,SEQID-00103, SEQID-00105, and SEQID-00298 were confirmed as beingexpressed from 293F cells but no visible bands could be detected in anyof the CHO-S cultures. SEQID-00363 could not be visualized on the gelfrom either 293F or CHO-S cultures. Supernatants from 293F cultures forSEQID-00001, SEQID-00103, SEQID-00105, SEQID-00298, and SEQID-00363 aswell as CHO-S supernatants for SEQID-00103 and SEQID-00105 were purifiedvia IMAC. SEQID-00103, SEQID-00105, and SEQID-00298 were scaled up to190 mL transfection volume in a 1 L shake flask using 293F cells.Transfection procedure was also scaled accordingly. 4×190 mL culturesfor both SEQID-00103 and SEQID-00105 and 2×190 mL cultures forSEQID-00298 were run. On Day 2 these cultures were fed with the 20%Phytone Peptone feed to a final concentration of 2% in culture and wereharvested on Day 5.

Example 17 Nutritive Polypeptide Expression Analysis

Nutritive polypeptides intracellularly expressed and/or secreted weredetected using a variety of methods. These methods includeelectrophoresis, western blot, dot-blot, ELISA, and quantitativeLC/MS/MS.

Electrophoresis Analysis. Extracellular and/or intracellular expressedproteins were analyzed by chip electrophoresis (Labchip GXII) orSDS-PAGE analysis to evaluate expression level.

For SDS-PAGE, 10 μl sample in Invitrogen LDS Sample Buffer mixed with 5%1-mercaptoethanol was boiled and loaded onto either: 1) a Novex® NuPAGE®12% Bis-Tris gel (Life Technologies), or 2) a Novex® 16% Tricine gel(Life Technologies), and run using standard manufacturer's protocols.Gels were stained using SimplyBlue™ SafeStain (Life Technologies) usingthe standard manufacturer's protocol and imaged using the MolecularImager® Gel Doc™ XR+ System (Bio-Rad). Over-expressed heterologousproteins were identified by comparison against a molecular weight markerand control cultures.

For chip electrophoresis (Labchip GX II) samples were analyzed using aHT Low MW Protein Express LabChip®, Kit (following the manufacturer'sprotocol) by adding 2 μl of sample to 7 μl sample buffer. A proteinladder was loaded every 12 samples for molecular weight determinationand quantification (molecular weight in kDa).

LC-MS/MS Analysis.

Whole cell, cell lysate and secreted samples can be analyzed for proteinexpression using LC-MSMS. To analyze samples, 10 g of sample were loadedonto a 10% SDS-PAGE gel (Invitrogen) and separated approximately 2 cm.The gel was excised into ten segments and the gel slices were processedby washing with 25 mM ammonium bicarbonate, followed by acetonitrile.Gel slices were then reduced with 10 mM dithiothreitol at 60° C.,followed by alkylation with 50 mM iodoacetamide at room temperature.Finally, the samples were digested with trypsin (Promega) at 37° C. for4 h and the digestions were quenched with the addition of formic acid.The supernatant samples were then analyzed by nano LC:‘MS’MS with aWaters NanoAcquity HPLC system interfaced to a ThermoFisher Q Exactive.Peptides were loaded on a trapping column and eluted over a 75 μmanalytical column at 350 nL/min; both columns were packed with JupiterProteo resin (Phenomenex). A 1 h gradient was employed. The massspectrometer was operated in data-dependent mode, with MS and MS/MSperformed in the Orbitrap at 70.000 FWHM resolution and 17,500 FWHMresolution, respectively. The fifteen most abundant ions were selectedfor MS/MS. Data were searched against an appropriate database usingMascot to identify peptides. Mascot DAT files were parsed into theScaffold software for validation, filtering and to create a nonredundantlist per sample. Data were filtered at 1% protein and peptide falsediscovery rate (FDR) and requiring at least two unique peptides perprotein.

Anti-FLAG Western Blot.

Extracellular and/or intracellular protein was analyzed using westernblot to evaluate expression level.

For SDS-PAGE, 10 μl sample in Invitrogen LDS Sample Buffer mixed with 5%1-mercaptoethanol was boiled and loaded onto a Novex® NuPAGE® 12%His-Tris gel (Life Technologies). For standards, 0.5 μg to 2 μgAmino-terminal FLAG-BAP™ Fusion Protein (Sigma) were loaded as apositive control. Gel electrophoresis was performed according tomanufacturer's protocol. Once run, the gel was transferred onto aniBlot® Mini Transfer Stack nitrocellulose 0.2 μm pore size membrane(Life Technologies) according to manufacturer protocol. Next, thenitrocellulose membrane was removed from the stack and assembled into aMillipore SNAP I.d.® 2.0 Protein Detection Apparatus. 30 ml of MilliporeBlok CH Noise Cancelling reagent was placed into an assembled reservoirtray and vacuumed through. 3 ml of antibody solution was prepared bydiluting 2 μl of Sigma Monoclonal ANTI-FLAG® M2-Peroxidase (HRP)antibody into 3 ml of Millipore Blok CH Noise Cancelling Reagent.Antibody solution was added to reservoir tray and allowed to incubatefor 10 minutes without vacuum. After incubation, the reservoir tray wasfilled with 90 ml of 1×PBS+0.1% Tween 20 and vacuumed through as thefinal wash step. After wash, the nitrocellulose membrane was removed andplaced into a reagent tray. 20 ml of Millipore Luminata Classico WesternHRP substrate was added and allowed to incubate for 1 minute. Afterincubation, the membrane was placed into imaging tray of Gel Doc™ XR+System (Bio-rad) and imaged using a chemiluminescent protocol.

Anti-FLAG Dot Blot.

Extracellular and/or intracellular proteins were analyzed using dot blotto evaluate expression level.

110 μl of 0.2 μm filtered sample was mixed with 110 μl 8.0 M GuanidineHydrochloride, 0.1 M Sodium Phosphate (Denaturing Buffer) to allow foreven protein binding. A standard curve of Amino-terminal FLAG-BAP™Fusion Protein (Sigma) was prepared in the same matrix as the samples,starting at 2 μg, diluting 2× serially to 0.0313 μg. Invitrogen 0.45 μmnitrocellulose membrane was pre-wet in 1×PBS buffer for 5 minutes andthen loaded onto Bio-Rad Dot Blot Apparatus, 300 μl of PBS was vacuumedthrough to further wet the membrane. Next, 200 μl the 1:1Sample:Denaturing Buffer mixture was loaded into each well and allowedto drain through the dot blot apparatus by gravity for 30 minutes. Next,a 300 μl PBS is wash was performed on all wells by vacuum followed byloading 300 μl of Millipore Blok CH Noise Cancelling reagent andincubating for 60 minutes. After blocking, membrane was washed with 300μl of 1×PBS+0.1% Tween 20. Next, antibody solution was prepared byadding 2.4 μl of Sigma Monoclonal ANTI-FLAG® M2-Peroxidase (HRP)antibody to 12 ml of Millipore Blok CH Noise Cancelling reagent (1:5000dilution). 100 μl of the resulting antibody solution was added to eachwell and allowed to incubate for 30 minutes by gravity. After antibodyincubation, three final washes were performed with 300 μl 1×PBS+0.1%Tween 20 by vacuum. After washes, nitrocellulose membrane was removedand placed into a reagent tray, 20 ml of Millipore Luminata ClassicoWestern HRP substrate was added and allowed to incubate for 1 minute.After incubation, membrane was placed into imaging tray of Gel Doc™ XR+System (Bio-rad) and imaged using a chemiluminescent protocol.

Anti-FLAG ELISA.

Protein expression was detected by direct ELISA using an anti-FLAGantibody. Briefly, a dilution series (0.005-10 μg/mL) of FLAG fusionprotein (Sigma) was prepared in 0.1 M NaHCO3 (pH 9.5). A dilution series(0.01-20 μg/mL) of FLAG fusion protein was also prepared in spent mediumfrom an empty fungus culture diluted 10-fold in 0.1 M NaHCO3 (pH 9.5).Experimental cultured medium samples were diluted 10-fold in 0.1 MNaHCO3 (pH 9.5). The FLAG fusion protein dilution series and theexperimental samples were then transferred (0.2 mL) to the wells of aNunc-immuno™ Maxisorp™ (Thermo) 96-well plate and incubated overnight at2-8° C. to facilitate protein adsorption. The following morning, plateswere rinsed three times with Tris-buffered saline (TBS) containing 0.05%TWEEN 80 (TBST). The wells were blocked from non-specific proteinbinding by incubation with 0.2 mL of 1% non-fat dried milk dissolved inTBST for 1 h at room temperature. The plates were rinsed three moretimes with TBST and then incubated at room temperature for 1 h with 0.2mL of the monoclonal antibody anti-FLAG M2-HRP (Sigma) diluted 1:2000 inblocking buffer. The plates were again rinsed three more times with TBSTbefore incubation with 0.2 mL % well of SIGMAFAST™ o-phenylenediaminedihydrocholride (OPD) (Sigma) for 30 min at room temperature. Thereaction was terminated with the addition of 0.05 mL/well of 1 M HCl andthe absorbance of samples was measured at 492 nm on a spectrophotometerequipped with a plate reader.

Example 18 Therapeutic Liquid Formulations of Nutritive Polypeptides

Nutritive polypeptide sequences were administered for therapeuticpurposes in a variety of liquid formulations. For example, theformulations utilized differ by protein concentration, solution pH,presence or absence of particulates, minerals, tastants, and/orexcipient additives. In therapeutic liquid formulations, theconcentration of protein ranges from 0.1% to 60% w/w in solution. Incertain instances, a lower concentration is preferable. For example,SEQID-00105 has been dosed as low as 10%. In some cases a higherconcentration is preferable. For example, SEQID-00105 and SEQID-00363were dosed as 35% solutions. In some cases a nutritive polypeptidesequence is dosed at its maximum solubility, which varies by protein andis generally in the range of 0.1% to 60% w/w. Both SEQID-00105 andSEQID-00363 were shown to be a soluble liquid at 50% w/w in solution. Intherapeutic liquid formulations, the solution pH generally ranges from 2to 11. Protein solubility is known to be a strong function of solutionpH (C. Tanford. Physical Chemistry of Macromolecules, p. 242, Wiley, NewYork, 1961.) In most cases, nutritive polypeptide sequences are leastsoluble at their isoelectric point (pI), and thus solution pH is oftenadjusted to be above or below the pI of the nutritive polypeptidesequence. This modulation of pH allows control over protein solubility.For example, SEQID-00105 and SEQID-00363 have isoelectric points near 4.These nutritive polypeptide sequences were purposely formulated at pH8-9, so they would be above their pI. For example, SEQID-00587 has a pIof 9.7 and was purposely formulated at pH 7, so that it would be belowits pI. Nutritive polypeptides that are soluble at their pI, can beformulated at their pI so that the liquid formulation does not requirean additional buffering species to maintain the solution pH. In thiscase, the protein itself acts to buffer the solution pH, as its ownamino acids are protonated and deprotonated. A protein solutionformulated at the pI of the protein shows resistance to changes in pHwhen acid or base are added, indicating that the solution is, in fact,buffered by the protein itself. In some therapeutic liquid formulations,a nutritive polypeptide includes particulate matter. Particulate matteris visible to the eye, and/or it contains subvisible particulates(example soluble aggregates). Particulate matter is product-related,and/or it is foreign. Particulate matter occurs in suspension, as aslurry, and/or settles at the bottom of the solution. In someembodiments, particulate matter is desirable because wherein it isindigestible or slowly digestible in the stomach, it acts as a carrierdelivering the nutritive polypeptide to the intestine. In someembodiments, particulate matter is desirable in a liquid formulationbecause it allows dosing the nutritive polypeptide above its limit ofsolubility. In the case of SEQID-00105, there is no visible particulatematter. SEQID-00424 was dosed with suspended particulate matter.

In therapeutic liquid formulations, a nutritive polypeptide sequence istypically formulated with one or more excipients dissolved in theformulation. Each excipient is included for a specific purpose. Buffers(examples: Tris, phosphate, ammonium bicarbonate, sodium carbonate,acetate, citrate, arginine) are added to control the solution pH. Sugarsare added to control aggregation and solubility (examples: trehalose,glucose, sucrose, and mannitol). Detergents are added to controlsolubility and aggregation (examples tween, triton, CHAPS, anddeoxycholate). Polyalcohols are added to control solubility andaggregation (glycerol, PEG). Chaotropes are added to increase proteinsolubility (example thiocyanate and urea). Antioxidants are added toprevent protein oxidation (examples ascorbic acid and methionine). Saltsare added to increase protein solubility and/or are added to achieve adesired osmolality (example sodium chloride). SEQID-00105, SEQID-00363,SEQID-00426 were formulated in sodium phosphate and sodium chloride anddosed orally. SEQID-00587 and SEQID-00559 were formulated in ammoniumbicarbonate and dosed orally. SEQID-00240 was formulated in sodiumcarbonate and dosed orally. Tastants were added to nutritivepolypeptides to enhance the gustatory experience of the user, withsuccessful result. Vanilla extract was added in combination withsucralose according to Tang et al. (Tang J E, Moore D R. Kujbida G W,Tarnopolsky M A, Phillips S M. J Appl Physiol (1985). 2009 September;107(3):987-92). The qualitative benefit of enhanced flavor wasdocumented by users as being “quite pleasant.”

The two tables Table E18A and Table E18B summarize a number ofadministrations of nutritive polypeptides to humans and to rats.

TABLE E18A Therapeutic liquid formulations of nutritive polypeptidesused for human administration. Human Administration Protein Conc dosedSEQID (g/L) (g) pH Buffer NaCl Tastants SEQID-00105 350 35 8.7 2 mM 6 mMEach formulation phosphate contained 8 mL of SEQID-00363 350 35 7 3 mM14 mM vanilla extract per phosphate liter and 4 grams SEQID-00105 117 208.7 2 mM 6 mM of sucralose per phosphate liter, according to SEQID-00105117 20 8.7 2 mM 6 mM Tang, et al. phosphate SEQID-00363 117 20 7 3 mM 14mM phosphate SEQID-00426 117 20 7 none none

TABLE E18B Therapeutic liquid formulations of nutritive polypeptidesused for human administration. Rat Administration dosage (mg protein perConc kg body SEQID (g/L) weight) pH Buffer NaCl SEQID-00105 250 2,8508.7 2 mM phosphate  6 mM SEQID-00105 250 2,850 8.7 2 mM phosphate  6 mMSEQID-00338 250 2,850 8.7 2 mM phosphate  6 mM SEQID-00338 250 2,850 8.72 mM phosphate  6 mM SEQID-00105 98 1,113 8.7 2 mM phosphate  6 mMSEQID-00240 135 1,539 10.8 25 mM Na2CO3  0 mM SEQID-00105 156 1,781 8.72 mM phosphate  6 mM SEQID-00363 229 2,850 7 3 mM phosphate 14 mM(a-mannosidase treated) SEQID-00363 250 2,850 7 3 mM phosphate 14 mM(hydrolyzed) SEQID-00105 250 2,850 8.7 2 mM phosphate  6 mM SEQID-00105250 2,850 8.7 2 mM phosphate  6 mM SEQID-00105 250 2,850 8.7 2 mMphosphate  6 mM SEQID-00105 250 2,850 8.7 2 mM phosphate  6 mMSEQID-00105 250 2,850 8.7 2 mM phosphate  6 mM SEQID-00338 250 2,850 8.72 mM phosphate  6 mM SEQID-00352 250 2,850 7 3 mM phosphate 14 mMSEQID-00363 250 2,850 7 3 mM phosphate 14 mM SEQID-00363 250 2,850 7 3mM phosphate 14 mM SEQID-00423 250 2,850 7 3 mM phosphate 14 mMSEQID-00424 250 2,850 7 3 mM phosphate 14 mM SEQID-00425 250 2,850 7 3mM phosphate 14 mM SEQID-00426 250 2,850 7 none  0 mM SEQID-00426 2502,850 7 none  0 mM SEQID-00429 250 2,850 7 3 mM phosphate 14 mMSEQID-00559 250 2,850 7.7 25 mM NH4HCO3  0 mM SEQID-00587 250 2,850 7.725 mM NH4HCO3  0 mM

Example 19 Therapeutic Formulations of Nutritive Polypeptides

Alternative to soluble, homogenous, liquid formulations, nutritivepolypeptides can be prepared alternatively. This example describesalternative nutritive polypeptide formulations such as slurries, gels,tablets and food ingredients.

Slurry Formulations.

Slurries are semiliquid mixtures that contain both soluble and insolublematerial which generally appear as fine granules in solution. Nutritivepolypeptide slurries are prepared when a nutritive polypeptide is eitherconcentrated above its maximum solubility, or, when a lyophilized orfreeze dried preparation of a nutritive polypeptide is resuspended aboveits maximum solubility. Optionally, addition of an emulsifier such assoy lecithin is added at a concentration between 0.1-1% to stabilize thehomogeneity of a slurry (van Nieuwenhuyzen et al., 1999 Eur. Journal ofLipid Sci, and Tech.).

Gel Formulations.

Alternatively, nutritive polypeptides are formulated as gels. Gels aresolid, jelly-like formulations that are generally formed throughmolecular cross linking. Nutritive polypeptides are formulated as gelsthrough treatment with transglutaminase (EC Number 2.3.2.13).Transglutaminase can catalyze the cross linking of nutritivepolypeptides between g-carboxamide groups of peptide bound glutamineresidues and the e-amino groups of nutritive polypeptide bound lysineresidues. This formation of a g-glutamyl-e-lysine cross links proteinsin solution; thus, promoting gel formation.

Human transglutaminase is a calcium (Ca2+) dependent enzyme with a Kdfor calcium in the range of 0.3-3 uM (Ahvazi et al., 2003 Journal ofBiological Chemistry). Due to the precipitave effects of calcium inpreparations of nutritive polypeptides, a microbial (Streptomycesmobaraensis) orthologue of transglutaminase has been identified thatacts in a calcium-independent manner (Ando et al, 1989 Agric Biol Chem).To prepare a gelatinous preparation of nutritive polypeptides, nutritivepolypeptides are solubly formulated at 250 g/L at neutral pH.Transglutaminase is spiked into the preparation at 10 EU per g nutritivepolypeptide and allowed to react at 35° C. until adequate gel formationhas occurred (Chen et al., 2003 Biomaterials).

Tablet Formulations.

Preparation of solid tablets of nutritive polypeptides is accomplishedaccording to Sakarkar et al. 2009 (International Journal of AppliedPharmaceutics). Tablets are formulated as a mixture of nutritivepolypeptides, excipients and binding agents. Tablets are composed of 50%w/w nutritive polypeptide, 26% w/w microcrystalline cellulose, 7.5w,sodium bicarbonate-citric acid mixture (70:30), 6.5% w/w lactose, 5.5%w/w, magnesium stearate and bound by 4.5% w/w polyvinyl pyrrolidonesolution in isopropanol. Tablets are dehumidified and granulated priorto compression into 100 mg tablets. Tablets are coated with 12.5% w/wethyl cellulose solution in dichloromethane and diethyl phthalate as aplasticizer.

Inhalable Dry Powder.

Nutritive polypeptides are formulated to be administered as an inhalabledry powder as described in Lucas et al., 1998 Pharm Res. Nutritiveproteins are co-processed with malto-dextrin by spray-drying to producemodel protein particles. Aerosol formulations are then prepared bytumble mixing protein powders with a-lactose monohydrate (63-90 μm) ormodified lactoses containing between 2.5 and 10% w/w fine particlelactose (FPL) or micronised polyethylene glycol 6000. Powder blends arethen characterized in terms of particle size distribution, morphologyand powder flow.

Conventional Food Formulations.

Nutritive polypeptides are formulated as a food ingredients as dry,solid formulations. For example, nutritive polypeptides are incorporatedinto pasta dough by mixing dry nutritive polypeptide formulations intowater, durum semolina. Arabica gum, mono- and diglycerides, fiber, yeastand citric acid. Dough is cut to shape, dried and packaged.

Example 20 In Vitro Screening of Amino Acids and Nutritive Polypeptidesfor GLP-1 Production

Glucagon-like peptide-1 (GLP-1) is a peptide hormone produced by L-cellsof the intestine in response to multiple nutrient stimuli. GLP-1 is anincretin that decreases blood glucose levels by increasing insulinrelease from the pancreas. GLP-1 acts on other peripheral tissuesincreasing glucose uptake and storage in skeletal muscle and adiposetissue, decreasing the rate of gastric emptying, and decreasing hepaticglucose production (Baggio LL & DJ Drucker. 2007. Biology of incretins:GLP-1 and GIP. Gastroenterology. 132:2131-2157). GLP-1 is a product ofthe post-translational cleavage of proglucagon to generate active GLP-1(7-36) this is rapidly degraded after secretion by dipeptidyl peptidaseIV (DPPIV) to GLP-1 (9-36).

Several mammalian gastrointestinal cell lines are used as models forL-cell secretion of GLP-1 (IEC-6 from rats, NCI-H716 and FHs74Int fromHumans, and STC-1 and GLUTag from mice). The purpose of theseexperiments is to determine which amino acid combinations, nutritiveprotein digests, and/or full length nutritive proteins induce GLP-1secretion in vitro.

The NCI-H716 cell line is obtained from the American Type CultureCollection (Catalog number ATCC. CCL-251™, Manassas, Va.). RPMI-1640,Dulbecco's Modified Eagle Medium (DMEM) and Dulbecco's PhosphateBuffered Saline (DPBS) are obtained from Life Technologies (Catalognumbers 11875, 11965 and 14190, respectively; Carlsbad, Calif.).Penicillin-Streptomycin Solution is obtained from ATCC (Catalog number30-2300, Manassas, Va.). Antibiotic-Antimycotic Solution (100×) isobtained from Sigma-Aldrich (Catalog number A5955, St. Louis, Mo.).Fetal bovine serum is obtained from GE Healthcare (Catalog numberSH3007103HI, Wilmington, Mass.). Bovine serum albumin is obtained fromFisher Scientific (Catalog number BPI600-100, Pittsburgh, Pa.).Fatty-acid free bovine serum albumin is obtained from Sigma-Aldrich(Catalog number A7030, St. Louis, Mo.). Phenylmethyl sulfonyl fluoride(PMSF), a protease inhibitor, is obtained from Thermo Scientific(Catalog number 36978, Waltham, Mass.). Diprotin A, a DPPIV inhibitor,is obtained from Sigma-Aldrich (Catalog number 19759, St. Louis, Mo.).Tissue Protein Extraction Reagent (T-PER) is obtained from ThermoScientific (Catalog number 78510, Waltham, Mass.). Active GLP-1concentration is determined using the AlphaLisa GLP-1 (7-36 amide)Immunoassay Research Kit (Catalog number AL215, PerkinElmer, Waltham,Mass.) and read on an EnSpire Alpha plate reader (PerkinElmer, Waltham,Mass.). Data are analyzed using Microsoft Excel version 14.0.7128.5000(Microsoft Corporation, Redmond. Wash.) and GraphPad Prism version 6.03for Windows (GraphPad Software, La Jolla, Calif.). Krebs Ringer Buffer(KRB) is prepared and the AlphaLISA GLP-1 (7-36 amide) ImmunoassayResearch Kit is obtained from PerkinElmer (Catalog number AL215.Waltham, Mass.).

Ninety-six well plates are pre-coated with MatriGel. 80 μL of MatriGelis added to 5 mL Dulbecco's Modified Eagle Medium (DMEM) withoutglucose. 50 μL are added per well and the plate incubated at 37° C. 5%CO2 for 30 minutes. MatriGel solution is aspirated prior to addition ofcells.

NCI-H716 cells are maintained in RPMI-1640 medium supplemented with 10%fetal bovine serum (FBS) and 1% Antibiotic-Antimycotic Solution andincubated in T-75 tissue culture flasks at 37° C., 5% CO2. Cells arepassaged 1:3 or 1:6 every 2 to 3 days.

Cells are detached with 0.25% trypsin-EDTA incubated at 37° C., 5% C02and centrifuged at 750 rpm for 10 minutes to pellet cells. Cell pelletis washed twice with 1× Dulbecco's Phosphate Buffered Saline (DPBS)supplemented with 1% FBS and centrifuged at 750 rpm for 10 minutes topellet cells. The cells are resuspended in Dulbecco's Modified EagleMedium (DMEM) supplemented with 10% FBS and 1% penicillin/streptomycinand counted on a hemocytometer. Cells are diluted to 1.8>106 cells/mLand 200 μL added to each well of a 96 well plate pre-coated withMatri-Gel. Cells are incubated for 2 days at 37° C., 5% CO2.

Screening of GLP-1 Secretion to Amino Acid Treatments in NCI-H716 Cells

Following two day incubation, medium is aspirated and replaced with 200μL Starvation Buffer [i.e. Krebs-Ringer Buffer (KRB) containing 50 μg/mLPMSF, 34 μg/mL Diprotin A, and 0.2% fatty-acid free bovine serum albumin(BSA)] and incubated for 30 minutes at 37° C., 5% CO₂. Starvation bufferis then aspirated and replaced with 100 μL/well of treatment article inStarvation Buffer. Cells are stimulated with treatment article for 2hours then medium is removed and frozen at −80° C. Treatment articlesinclude individual amino acids, amino acid blends, nutritive proteindigests, and/or full length nutritive proteins.

Determination of Active GLP-1 Concentration from Supernatant.

Supernatant is assayed for the active form of GLP-1 (7-36)NH2 using theAlphaLISA GLP-1 (7-36 amide) Immunoassay Research Kit (PerkinElmer,AL215) in accordance with the manufacturer's instructions. The standardis assayed in Assay Buffer supplemented to an equivalent concentrationof Starvation Buffer. Alternatively, the active form of GLP-1 ismeasured using an enzyme-linked immunosorbant assay (ELISA) as describedherein. Luminescence data from the AlphaLISA GLP-1 (7-36 amide)Immunoassay or GLP-1 ELISA is analyzed on Microsoft Excel and GraphPadPrism.

Duplicate sample concentrations are determined by non-linear regressionusing a 4 parameter logistic model of the standard following an x=log(x)transformation of the active GLP-1 concentration in GraphPad Prism 6.ANOVA and multiple comparison tests are conducted on GraphPad Prism 6.

Comparisons of the GLP-1 content from samples collected after testarticle treatment to those collected after vehicle control treatmentdescribe the degree of GLP-1 secretion due to a test article over time.Comparison of this difference across treatments describes thedifferential effects of each amino acid., amino acid blend, nutritiveprotein digest, and nutritive protein treatment relative to the other,and provides a means of ranking their efficacy.

GLP-1 secretion by amino acids

Cells were starved of amino acids as described herein and stimulatedwith stimulation buffer alone, 19 amino acids, 17 amino acids (withoutleucine, isoleucine or valine). 20 amino acids or leucine alone at theirconcentration in DME/F12 medium (see Table E20C) for two hours.Supernatant was harvested and frozen at −80° C. GLP-1 (7-36) amideconcentration was assayed subsequently. FIG. 6 shows supernatantconcentration of GLP-1 (7-36) detected in the supernatant followingstimulation, error bars are the standard deviation of the technicalreplicates. Fourteen compositions increased the concentration of GLP-1above 10% greater than that observed in the larger buffer onlystimulation (those lacking either Asn, Met, Gln, Tyr, His, Gly, Cys,Phe, Trp, Ala, Glu, Leu, Ile and Val). Two compositions, amino acidslacking Arg & Leu only treatment, showed decreased concentration ofGLP-1 (7-36) below 10% below the lower buffer only stimulation.

TABLE E20A Amino Acids μM Amino Acids μM Glycine 250 L-Leucine 451L-Alanine 50 L-Lysine 500 L-Arginine 700 L-Methionine 116 L-Asparagine57 L-Phenylalanine 215 L-Aspartic Acid 50 L-Proline 150 L-Cysteine 100L-Serine 250 L-Glutamic Acid 100 L-Threonine 449 L-Glutamine 2500L-Tryptophan 44 L-Histidine 150 L-Tyrosine 214 L-Isoleucine 416 L-Valine452

Example 21 Use of Nutritive Polypeptides to Improve Glycemic Control inHealthy, Fasted Rats

Glucose tolerance tests are a common method of measuring glycemiccontrol in both clinical and preclinical settings. During the test, alarge dose of glucose is given and blood samples are taken at subsequenttime points to determine how quickly blood glucose levels renormalize.In an oral glucose tolerance test (OGTT), a dose of glucose is ingestedby mouth. Such tests are clinically used to identify individuals withpoor glucose control (Cobelli et al., 2014), and pre-clinically toassess the therapeutic efficacy of anti-diabetes medications (Wagman &Nuss, 2001)(Moller, 2001). Glucose levels are modulated by a number ofdifferent gastrointestinal hormones, including insulin, glucagon,somatostatin, glucose-dependent insulinotropic peptide (GIP), andglucagon-like peptide 1 (GLP-1), which both directly and indirectlymodulate glucose levels. Combined measurements of glucose andgastrointestinal hormones are used to assess glucose intolerance,insulin resistance, and the severity of metabolic disease (Ferrannini &Mari, 2014).

An OGTT was performed on twenty five healthy, fasted, maleSprague-Dawley rats with indwelling jugular vein catheters (JVC) toassess the acute effects of nutritive polypeptide dosing on glycemiccontrol as well as insulin and GLP-I levels.

Oral Glucose Tolerance Test.

All rodents were approximately 10-12 weeks old, weighed average ofapproximately 350 g and acclimated for 4 days prior to testing. Animalswere housed singly with bedding and fed a regular rodent chow diet (LabDiet 5001) prior to the study. Housing temperature was at kept at 222°C., humidity at 50±20%, and a 12 hour light/2 hour dark cycle wasimplemented. Air circulation was ten or more air changes per hour with100% fresh air. Prior to treatment, all rats were fasted overnight forfourteen hours. Fasted animals were treated with formulations ofnutritive polypeptides dissolved in water by oral gavage (see TableE21A), and fifteen minutes after treatment gavage were then challengedwith an oral gavage of glucose (2 g/kg). Blood glucose was measured andblood was collected at seven time points (−15, 0, 15, 30, 60, 90, 120minutes relative to the glucose challenge). Blood was collected in anEDTA collection tube containing plasma stablizers (a DPP4 inhibitor anda protease cocktail inhibitor). One additional rat was sacrificed at andbled out to provide naïve blood for analytical standards. Glucose wasmeasured using small drops of blood collected via the JVC using aglucometer (AlphaTrak 2, Abbott).

TABLE E21A Dose Average Total Glucose Glucose Glucose Dose Conc. VolumeBW Protein Volume Dose Conc. Group (mg/kg) (mg/mL) (mL/kg) (kg) (mg)(mL/kg) (g/kg) (mg/mL) Vehicle NA NA 11.4 0.35 NA 4 2 500 SEQID- 2850250 11.4 0.35 5,985 4 2 500 00105 Arginine 1000 87.7 11.4 0.35 2,100 4 2500 HCl SEQID- 2850 250 11.4 0.35  5,985* 4 2 500 00338

Approximately 300 μL of blood was collected from the V of all rats inGroup 1-4 at six time points (−15, 0, 15, 30, 60, and 120 minutes).Glucose gavages and blood collections were timed to take the same amountof time per animal so that sample times were accurate for each animal.All time points were collected within 5% of the target time. Blood wascollected into pre-chilled (0-4° C.) K2EDTA blood collection tubescontaining Protease Inhibitor Cocktail (Catalog number D8340,Sigma-Aldrich, St. Louis, Mo.) and DPPIV inhibitor (Millipore,Billerica, Mass.) added to the tubes at 1:100 prior to collection. Afterblood collection, blood samples were maintained chilled (2-6° C.) andcentrifuged within 30 minutes. The collected plasma was placed in sampletubes and immediately stored at −80° C.

Prior to immunoassay analysis samples were thawed on ice for 1 hour,mixed thoroughly by pipette, rearrayed to 96 well microplates. Separatealiquots were prepared for insulin immunoassay and GLP-1 immunoassay.Master plate and aliquots were stored frozen at −80° C.

FIG. 7 shows the average blood glucose values during the OGTT describedherein. The error bars shown are the standard errors of the mean. Allgroups showed significant differences in blood glucose from fasting attimes t=15, and t=30 min after the glucose challenge (p<0.05, Dunnettmultiple comparison test). The groups that received SEQID-00105 andSEQID-00338 showed a significant difference in blood glucose relative tovehicle at times t=15, and t=30 after the glucose challenge (p<0.05.Tukey-Kramer multiple comparison test, comparing treatment group to eachother at each time point). These data indicated that acute ingestion ofSEQID-00105 and SEQID-00338 can significantly improve glycemic controlafter a glucose challenge in outbred male Sprague-Dawley rats.

The area under curve for blood glucose was calculated using theLinear-Log Traperoidal Method in Microsoft Excel, and statisticalanalysis was conducted on GraphPad Prism 6.

The area under curve for blood glucose integreated from 0-120 minutesand from 0-60 minutes (FIG. 8) show that acute dosing of SEQID-00105 andSEQID-00338 improves blood glucose control by reducing blood glucoseexcursion in the context of an oral glucose tolerance test. Between 0and 60 minutes both SEQID-00105 and SEQID-00338 have significantlysmaller change in blood glucose in comparison to vehicle (P<0.05,Dunnett's multiple comparisons test).

Rat Insulin Enzyme Linked Immunosorbent Assay (ELISA).

An Ultra-Sensitive Rat Insulin ELISA Kit was obtained from Crystal Chem,Inc. (Catalog number 90060, Downers Grove, Ill.). Plates were washedusing a BioTek ELx50 microplate strip washer (BioTek, Winooski, Vt.).Absorbance was read on a Synergy Mx monochromator-based microplatereader (BioTek, Winooski, Vt.). Data was analyzed using Microsoft Excelversion 14.0.7128.5000 (Microsoft Corporation, Redmond, Wash.) andGraphPad Prism version 6.03 for Windows (GraphPad Software, La Jolla,Calif.).

The ELISA kit was prewarmed to room temperature for 30 minutes prior tobeginning the assay set up. The standard curve dilutions were preparedin accordance with the manufacturer's instructions for running the assayin Wide Range format.

Plasma matrix from the naïve group and sample plasma were thawed on iceand then centrifuged at approximately 1000×rcf for 10 minutes at 4° C.to pellet any insoluble material.

Matrix Assay Buffer for running the insulin standard was prepared usingplasma matrix from the naïve group to a concentration of 5.26% in 95 μL.95 μL of Assay Buffer was added to all sample wells, and 95 μL of MatrixAssay Buffer was added to all standard wells. 5 μL of each sample andstandard were added in duplicate. The plates were incubated at 4° C. for2 hours. The plates were then washed five times with 300 μL/well 1× WashBuffer. The plates were tapped sharply several times on paper towels toremove any residual wash buffer.

Anti-insulin Enzyme Conjugate Working Solution was prepared by combining2 volumes Anti-Insulin Enzyme Conjugate Stock with 1 volume EnymeConjugate Diluent, and mixing by pipetting up and down and gentlyvortexing. 100 μL/well of Anti-Insulin Enzyme Conjugate Working Solutionwas added to all wells. The plates were sealed and incubated at roomtemperature for 30 minutes and then washed seven times with 300 μL/well1× Wash Buffer. The plates were tapped sharply several times on papertowels to remove any residual wash buffer. 100 μL/well Enzyme SubstrateSolution was then added to each well and incubated in the dark at roomtemperature for 40 minutes. 100 μL/well Stop Solution was added to allwells.

The absorbance was read on the Synergy Mx plate reader at 450 nm and 630nm. Final values obtained were the A450 nm-A630 nm values.

The insulin standard curve was corrected for matrix concentration ofinsulin by subtracting the mean of the 0 ng/mL insulin standard fromeach of the standard well A450 nm-A630 nm values in Excel. Duplicatesample concentrations were determined by non-linear regression using a 4parameter logistic model of the background corrected standard followingan x=log(x) transformation of insulin concentration in GraphPad Prism 6.ANOVA and multiple comparison tests were conducted on GraphPad Prism 6.The area under curve was integrated using the Linear-Log TrapezoidalMethod on Microsoft Excel, with post hoc testing conducted in GraphPad.

FIG. 9 shows the average plasma insulin concentration for n=6 rats pertreatment group over the course of the experiment. The error bars showthe standard error of the mean. All treatment groups had statisticallysignificant increases in plasma insulin relative to their treatment orvehicle gavage at 15, 30 and 60 minutes following the glucose challenge(Dunnett's multiple comparisons test). Only SEQID-00105 had astatistically significant increase in plasma insulin concentration atthe time of the glucose challenge (0) relative to the plasma insulin atthe time of the treatment gavage (P<0.0001, Dunnett's multiplecomparisons test). Both SEQID-00105 and SEQID-00338 had statisticallysignificant greater insulin concentrations at 120 minutes following theglucose challenge (P<0.05 and P<0.01, respectively; Dunnett's multiplecomparisons test).

In comparison to the vehicle, only SEQID-00105 showed a statisticallysignificantly greater increase in plasma insulin concentration at thetime of the glucose challenge (P<0.001, Dunnett's multiple comparisonstest).

These data indicated that an acute ingestion of SEQID-00105 canstimulate insulin release within 15 minutes of ingestion in outbred maleSprague-Dawley rats.

FIG. 10 shows the area under curve integrated between 0-240 and 0-60minutes for all treatment groups. No treatment group was statisticallysignificantly greater than vehicle.

Total GLP-1 Enzyme Linked Immunosorbent Assay (ELISA).

A rat GLP-1 ELISA Kit was obtained from Crystal Chem, Inc. (Catalognumber 81507, Downers Grove, Ill.). Plates were washed using a BioTekELx50 microplate strip washer (BioTek. Winooski, Vt.). Absorbance wasread on a Synergy Mx monochromator-based microplate reader (BioTek.Winooski Vt.). Data was analyzed using Microsoft Excel version14.0.7128.5000 (Microsoft Corporation. Redmond, Wash.) and GraphPadPrism version 6.03 for Windows (GraphPad Software, La Jolla, Calif.).

The ELISA kit was prewarmed to room temperature for 30 minutes prior tobeginning the assay set up. The standard curve dilutions were preparedin accordance with the manufacturer's instructions.

Plasma matrix from Group 5 and sample plasma were thawed on ice and thencentrifuged at approximately 1000× rcf for 10 minutes at 4° C. to pelletany insoluble material.

Matrix Assay Buffer for running the GLP-1 standard was prepared usingplasma matrix from the naïve group to a concentration of 25% in 100 μL.The ELISA microplates were washed three times with 350 μL/well 1× WashBuffer and tapped sharply on paper towels to remove residual washbuffer. 100 μL of Assay Buffer was added to all sample wells, and 100 μLof Matrix Assay Buffer was added to all standard wells. 25 μL of eachsample and standard were added in duplicate. Wells were mixed bypipetting. The plates were covered with adhesive foil and incubated for18 hours at room temperature on a horizontal plate shaker at 100 rpm.The plates were then washed three times with 350 μL/well 1× Wash Bufferthen tapped sharply several times on paper towels to remove any residualwash buffer. 100 μL/well of Biotin Labeled Antibody Solution was addedto all wells. The plates were then sealed and incubated at roomtemperature for 1 hour on a horizontal plate shaker at 100 rpm. Theplates were then washed three times with 350 μL/well 1× Wash Buffer thentapped sharply several times on paper towels to remove any residual washbuffer. 100 μL/well SA-HRP Solution was added to all wells. The plateswere then sealed and incubated at room temperature for 30 minutes on ahorizontal plate shaker at 100 rpm. The plates were then washed threetimes with 350 μL/well 1× Wash Buffer then tapped sharply several timeson paper towels to remove any residual wash buffer. 100 μL/well EnzymeSubstrate Solution was added to all wells. The plates were then sealedand incubated in the dark, without shaking, for 30 minutes at roomtemperature. Following substrate incubation, 100 μL Stop Solution wasadded to all wells.

The absorbance values were read on the Synergy Mx plate reader at 450 nmand 630 nm. Final values obtained were the A450 nm-A630 nm values.

The standard curve was corrected for matrix concentration of total GLP-1by subtracting the mean of the 0 μM GLP-1 standard from each of thestandard well A450 nm-A630 nm values in Excel. Duplicate sampleconcentrations were determined by non-linear regression using a 4parameter logistic model of the background corrected standard followingan x=log(x) transformation of GLP-1 concentration. ANOVA and multiplecomparison tests were conducted using GraphPad Prism 6. The area undercurve was integrated using the Linear-Log Trapezoidal Method onMicrosoft Excel, with post hoc testing conducted in GraphPad.

FIG. 11 shows average plasma GLP-concentration for n=6 rats pertreatment group over the course of the experiment. The error bars shownhere correspond to the standard error of the mean. The SEQID-00338treatment group shows a statistically significant greater concentrationof GLP-1 at the time of the glucose challenge than vehicle (p<0.0005,Dunnett's multiple comparisons test).

Example 22 Use of Nutritive Polypeptides to Improve Glycemic Control inZucker Fatty (fa/fa) Rats

An OGTT was performed in 18, fasted, male Zucker fatty rats withindwelling jugular vein catheters (JVC) to assess the acute effects ofnutritive polypeptide dosing on glycemic control as well as insulin andGLP-1 levels.

Oral Glucose Tolerance Test.

All rodents were approximately 10-11 weeks old, weighed average ofapproximately 450 g and acclimated for 4 days prior to testing. Animalswere housed singly with bedding and fed a regular rodent chow diet (LabDiet 5001) prior to the study. Housing temperature was at kept at 222°C., humidity at 50±20%, and a 12 hour light/2 hour dark cycle wasimplemented. Air circulation was ten or more air changes per hour with100% fresh air. Prior to treatment, all rats were fasted overnight forfourteen hours. Fasted animals were treated with formulations ofnutritive polypeptides dissolved in water by oral gavage (see TableE22A), and fifteen minutes after treatment gavage were then challengedwith an oral gavage of glucose (5 g/kg). Blood glucose was measured andblood was collected at seven time points (−15, 0, 15, 30, 60, 90, 120minutes relative to the glucose challenge). Blood was collected in anEDTA collection tube containing plasma stablizers (a DPP4 inhibitor anda protease cocktail inhibitor). One additional rat was sacrificed at andbled out to provide naïve blood for analytical standards. Glucose wasmeasured using small drops of blood collected via the JVC using aglucometer (AlphaTrak 2, Abbott).

TABLE E22A Body Polypeptides weight Dose Volume Glucose Group (average,g) SEQID (mg/kg) (ml/kg) Dose (g/kg) 1 450 Vehicle 0 11.4 5 2 450 001052850 11.4 5 3 450 00338 2850 11.4 5

Approximately 300 μL of blood was collected from the JVC of all rats inGroup 1-3 at six time points (−15, 0, 15, 30, 60, 90, and 120 minutes).Glucose gavages and blood collections were timed to take the same amountof time per animal so that sample times were accurate for each animal.All time points were collected within 5% of the target time. Blood wascollected into pre-chilled (0-4° C.) K2EDTA blood collection tubescontaining Protease Inhibitor Cocktail (Catalog number D8340.Sigma-Aldrich, St. Louis. Mo.) and DPPIV inhibitor (Millipore,Billerica, Mass.) added to the tubes at 1:100 prior to collection. Afterblood collection, blood samples were maintained chilled (2-6° C.) andcentrifuged within 30 minutes. The collected plasma was placed in sampletubes and immediately stored at −80° C.

Prior to immunoassay analysis samples were thawed on ice for 1 hour,mixed thoroughly by pipette, rearrayed to 96 well microplates. Separatealiquots were prepared for insulin immunoassay and GLP-1 immunoassay.Master plate and aliquots were stored frozen at −80° C.

FIG. 12 shows the average blood glucose values during the OGTT describedherein. The error bars shown are the standard errors of the mean.

The integrated area under curve (AUC) was calculated on Microsoft Excelusing the Linear-Log Trapezoidal Method and statistical testing wasconducted on GraphPad Prism 6.03.

FIG. 13 shows the integrated AUC for each treatment group between thetime of glucose challenge (0 min.) and 60 minutes, and between time 0and 120 minutes. No treatment showed statistically significantdifference from vehicle between time 0 and 60 minutes. Between time 0and 120 minutes SEQID-00105 but not SEQID-00338 shows a statisticallysignificant decrease in integrated area under curve compared to vehicle(P<0.005, Dunnett's multiple comparisons test). These data show thatacute dosing of SEQID-00105 can reduce glucose excursion due to an oralglucose challenge in a Zucker Fatty (fa/fa) model rodent model.

Rat Insulin Enzyme Linked Immunosorbent Assay (ELISA).

An Ultra-Sensitive Rat Insulin ELISA Kit was obtained from Crystal Chem,Inc. (Catalog number 90060, Downers Grove, Ill.). Plates were washedusing a BioTek ELx50 microplate strip washer (BioTek. Winooski. Vt.).Absorbance was read on a Synergy Mx monochromator-based microplatereader (BioTek, Winooski. Vt.). Data was analyzed using Microsoft Excelversion 14.0.7128.5000 (Microsoft Corporation, Redmond, Wash.) andGraphPad Prism version 6.03 for Windows (GraphPad Software, La Jolla,Calif.).

The ELISA kit was prewarmed to room temperature for 30 minutes prior tobeginning the assay set up. The standard curve dilutions were preparedin accordance with the manufacturer's instructions for running the assayin Wide Range format.

Plasma matrix from the naïve group and sample plasma were thawed on iceand then centrifuged at approximately 1000× rcf for 10 minutes at 4° C.to pellet any insoluble material.

Matrix Assay Buffer for running the insulin standard was prepared usingplasma matrix from the naïve group to a concentration of 5.26% in 95 μL.95 μL of Assay Buffer was added to all sample wells, and 95 μL of MatrixAssay Buffer was added to all standard wells. 5 μL of each sample andstandard were added in duplicate. The plates were incubated at 4° C. for2 hours. The plates were then washed five times with 300 μL/well 1× WashBuffer. The plates were tapped sharply several times on paper towels toremove any residual wash buffer.

Anti-insulin Enzyme Conjugate Working Solution was prepared by combining2 volumes Anti-Insulin Enzyme Conjugate Stock with 1 volume EnymeConjugate Diluent, and mixing by pipetting up and down and gentlyvortexing. 100 μL/well of Anti-Insulin Enzyme Conjugate Working Solutionwas added to all wells. The plates were sealed and incubated at roomtemperature for 30 minutes and then washed seven times with 300 μL/well1× Wash Buffer. The plates were tapped sharply several times on papertowels to remove any residual wash buffer. 100 μL/well Enzyme SubstrateSolution was then added to each well and incubated in the dark at roomtemperature for 40 minutes. 100 μL/well Stop Solution was added to allwells.

The absorbance was read on the Synergy Mx plate reader at 450 nm and 630nm. Final values obtained were the A450 nm-A630 nm values. Samples inwhich the value exceeded the standard curve were rerun at 1:1 dilutionagainst a 2.5% matrix standard

The insulin standard curve was corrected for matrix concentration ofinsulin by subtracting the mean of the 0 ng/mL insulin standard fromeach of the standard well A450 nm-A630 nm values in Excel. Duplicatesample concentrations were determined by non-linear regression using a 4parameter logistic model of the background corrected standard followingan x=log(x) transformation of insulin concentration in GraphPad Prism 6.ANOVA and multiple comparison tests were conducted on GraphPad Prism 6.The area under curve was integrated using the Linear-Log TrapezoidalMethod on Microsoft Excel, with post hoc testing conducted in GraphPad.

FIG. 14 shows the average plasma insulin concentration for n=6 rats pertreatment group in Vehicle & SEQID-00105 and n=5 rats per treatmentgroup in the case of SEQID-00338 over the course of the experiment.One-way ANOVA with Dunnett's multiple comparisons tests were used tocompare within each treatment to time 0 and between treatments at thesame time point to vehicle. Vehicle had no statistically significantchange in plasma insulin compared to the time of vehicle gavage.SEQID-00105 had statistically significantly greater plasma insulincompared to the time of treatment gavage (time −15) at the time of theglucose challenge (time 0) and at 15 minutes and 90 minutes followingglucose challenge (P=0.0002, P<0.05 and P<0.05, respectively).SEQID-00338 had statistically significantly greater plasma insulinconcentration compared to the time of treatment gavage at all subsequentsampled time points (P<0.0001, P<0.05, P<0.005, P<0.005, and P=0.0005,respectively).

In comparisons between treatments, neither SEQID-00105 nor SEQID-00338was significantly different from Vehicle at the time of treatment orvehicle gavage. At the time of the glucose challenges and all subsequenttime points sampled (0, 15, 30, 60 and 90 minutes) both SEQID-00105 andSEQID-00338 had a significantly greater plasma insulin concentrationthan vehicle. This shows that both treatments stimulate insulinsecretion in the Zucker Fatty (fa/fa) model.

FIG. 15 shows the integrated area under the curve for each group. OnlySEQID-00338 treatment integrated between 0 and 90 minutes wasstatistically significantly greater than vehicle (P<0.005).

Active GLP-1 Enzyme Linked Immunosorbent Assay (ELISA). A rat activeGLP-1 ELISA Kit was obtained from Eagle Biosciences (Catalog numberGP121-K01, Nashua, N.H.). Plates were washed using a BioTek ELx50microplate strip washer (BioTek, Winooski, Vt.). Absorbance was read ona Synergy Mx monochromator-based microplate reader (BioTek, Winooski,Vt.). Data was analyzed using Microsoft Excel version 14.0.7128.5000(Microsoft Corporation. Redmond, Wash.) and GraphPad Prism version 6.03for Windows (GraphPad Software, La Jolla, Calif.).

The ELISA kit was prewarmed to room temperature for at least 30 minutesprior to beginning the assay set up. The standard curve dilutions wereprepared in accordance with the manufacturer's instructions.

Plasma matrix from Group 5 and sample plasma were thawed on ice and thencentrifuged at approximately 1000× rcf for 10 minutes at 4° C. to pelletany insoluble material.

Matrix Assay Buffer for running the active GLP-1 standard was preparedusing plasma matrix from the naïve group to a concentration of 10% in100 μL for samples tested at 1:1 dilution or 20% in 100 μL for samplestested undiluted. 20 μL of standards and samples were added to thepre-coated microplate and 100 μL appropriate assay buffer added to thestandard and sample wells. The plates were covered with adhesive foiland incubated for 24 hours at 4° C. protected from light. The plateswere then washed five times with 350 μL/well 1× Wash Buffer then tappedsharply several times on paper towels to remove any residual wash buter. 100 μL/well of ELISA HRP Substrate was added to all wells. Theplates were then sealed and incubated at room temperature for 20 minutesprotected from light. 100 μL/well ELISA Stop Solution was added to allwells and gently mixed.

The absorbance values were read on the Synergy Mx plate reader at 450 nmand 620 nm. Final values obtained were the A450 nm-A620 nm values.

The standard curve was corrected for matrix concentration of activeGLP-1 by subtracting the mean of the 0 μM GLP-1 standard from each ofthe standard well A450 nm-A620 nm values in Excel. Duplicate sampleconcentrations were determined by non-linear regression using a 4parameter logistic model of the background corrected standard followingan x=log(x) transformation of GLP-1 concentration. ANOVA and multiplecomparison tests were conducted using GraphPad Prism 6. The area undercurve was integrated using the Linear-Log Trapezoidal Method onMicrosoft Excel, with post hoc testing conducted in GraphPad.

FIG. 16 shows average plasma GLP-1 concentration for n=6 rats pervehicle and SEQID-00105, and n=5 rats per SEQID-00338 treatment group,over the course of the experiment. One-way ANOVA with Dunnett's multiplecomparisons tests were used to compare within each treatment to time 0and between treatments at the same time point to vehicle. Vehicle showedno significant difference in GLP-1 (7-36) concentration at any timepoint after vehicle gavage. SEQID-00105 showed significantly greaterGLP-1 (7-36) concentration at 15 minutes and 30 minutes after glucosechallenge (P<0.0001 and P<0.05, respectively). SEQID-00338 had asignificantly greater GLP-1 concentration at 15 minutes followingglucose challenge (P<0.005).

When compared to vehicle at each time point only SEQID-00105 had asignificantly greater GLP-1 (7-36) concentration than vehicle at 15minutes following glucose challenge (P<0.005).

FIG. 17 shows the area under curve for GLP-1 (7-36) for each treatmentgroup integrated to 0-90 and 0-60 minutes. No treatment had asignificantly different GLP-1 (7-36) integrated AUC compared to vehicleat either 0-90 or 0-60 minutes.

In another experiment, an OGTT was performed in 24, fasted, male Zuckerfatty rats with indwelling jugular vein catheters (JVC) to assess theacute effects of nutritive protein dosing on glycemic control as well asinsulin and GLP-1 levels. The capacity of SEQID-00105 to improve glucosecontrol was tested by comparing the blood glucose excursion ofSEQID-00105 to alogliptin to SEQID-00105+ alogliptin to vehicle in thecontext of an oral glucose tolerance test. All rodents wereapproximately 10-11 weeks old, weighed average of approximately 430 gand acclimated for 4-5 days prior to testing. Prior to treatment, allrats were fasted overnight for fourteen hours. Fasted animals weretreated with formulations of nutritive proteins dissolved in water byoral gavage (see table E22B), and fifteen minutes after treatment gavagewere then challenged with an oral gavage of glucose (2 g/kg). Bloodglucose was measured and blood was collected at nine time points (−15,0, 15, 30, 60, 90, 120, 180 and 240 minutes relative to the glucosechallenge).

TABLE E22B Body DPP TV weight Polypeptides Inhibitor Glucose (average,Treatment Dose Volume Dose Dose Group g) ID (mg/kg) (ml/kg) (mg/kg)(g/kg) 1 430.5 Vehicle 0 11.4 0 2 2 432.3 SEQID-00105 2850 11.4 0 2 3431.7 Alogliptin 0 11.4 0.3 2 4 435.5 SEQID-00105 + 2850 11.4 0.3 2Alogliptin

FIG. 18 shows the average blood glucose values during the OGTT describedherein. N=6 rats per treatment group. The error bars shown are thestandard errors of the mean. Each group was compared post hoc onGraphPad Prism 6, two-way ANOVA, Dunnett's multiple comparisons testfirst comparing within each group to the fasting glucose concentration,followed by a comparison of each time point to vehicle. No treatmentgroup blood glucose was significantly different from fasting at the timeof the glucose challenge.

Fasting glucose and blood glucose at the time of the glucose challengewas not significantly different between each group and vehicle. At 15minutes following glucose challenge, SEQID-00105 only and SEQID-00105+Alogliptin had significantly lower blood glucose compare to vehicle(P=0.0003 & P<0.0001, respectively). At 30 minutes following the glucosechallenge Alogliptin alone and SEQID-00105+ Alogliptin had significantlylower blood glucose than vehicle (P=0.0424 & P=0.0021, respectively). At60 minutes following the glucose challenge, only Alogliptin alone wassignificantly lower than vehicle (P<0.0001). No group after 60 minuteshad significantly different blood glucose than vehicle.

The integrated area under curve (AUC) was calculated on Microsoft Excelusing the Linear-Log Trapezoidal Method and two-way ANOVA and Dunnett'smultiple comparisons tests was conducted on GraphPad Prism 6.03. Notreatment showed statistically significant difference in glucose AUCfrom vehicle between time 0 and 60 minutes. Between time 0 and 120minutes and between time 0 and 240 minutes only the alogliptin alonetreatment was significantly less than vehicle (P=0.0051 & P=0.0054,respectively).

Example 23 Use of Nutritive Polypeptides to Improve Glycemic Control andFasting Glucose in Diet Induced Obese Mice

The effects of chronic dosing of therapeutic nutritive polypeptidesdescribed herein are evaluated by oral glucose tolerance tests in dietinduced obese (DIO) mice. In particular, chronic dosing in this animalmodel of metabolic disease can affect glycemic control, insulinresistance, fasting glucose and insulin levels, and comparison offasting levels as well as glucose area under the curve (AUC) during anOGTT before and after a period of daily dosing provides a measure ofcompound efficacy.

Four groups of 10 male C57BL/6 mice are fed a high fat diet ad libitumfor 14 weeks to ensure that they develop elevated fasting glucose levels(hyperglycemia), elevated fasting insulin levels (hyperinsulinemia), andimpaired glucose control (Xu. H. et al. Chronic inflammation in fatplays a crucial role in the development of obesity-related insulinresistance. J. Clin. Invest. (2003) 112: 1821-1830). A single group of10 male C57BL/6 mice (group I) is fed a normal diet for comparison oftreatment arms on HFD to normal diet at the same age, handling, andhousing conditions. All mice are housed and acclimated for three daysprior to the start of the study.

All Mice are fasted overnight for fourteen hours before OGTT treatment,and a blood sample is collected the morning of the study prior to dosingfor analysis of fasting glucose and hormone levels. Fasted animals aretreated with formulation of provided nutritive polypeptides by oralgavage fifteen minutes before glucose challenge. Glucose (2 g/kg) isorally administered at time zero. Blood glucose is measured at seventime points (−15, 0, 15, 30, 60, 90, 120 minutes). Age-matched normalmice under regular diet are used as an internal standard for theanalytics. In groups 2-5, mice receive daily dose of providedtherapeutic nutritive polypeptides (2.85 g/kg) (groups 4 and 5) orvehicle control (groups 2 and 3) for 15-30 days via daily gavage orformulation into chow. All blood is collected in an EDTA collection tubecontaining plasma stabilizers (a DPP4 inhibitor and a protease cocktailinhibitor), processed for plasma, and stored frozen at −80C.

An OGTT as described above is performed again on the final day of thestudy with either vehicle (groups 2 and 4) or test article (groups 1, 3,and 5). Prior to the final test article or vehicle dose, a blood sampleis collected for analysis of fasting glucose and hormone levels. At thecompletion of the final OGTT, all mice are sacrificed and entire bloodvolume is collected via cardiac puncture. Analysis of insulin levels areperformed using an ELISA method described herein.

Comparisons of end of study OGTT glucose AUC across groups 2 and 4describe the effect of chronic test article administration without theacute effects of test article administration on the OGTT. Comparisons ofend of study OGTT glucose AUC across groups 3 and 5 describe the effectof chronic test article administration and include the acute effects oftest article administration on the OGTT. Comparisons of fasting glucoseand insulin levels at the beginning and end of the study within group 4or within group 5 describe the effect of chronic dosing on fastingglucose and insulin levels.

Example 24 Use of Nutritive Polypeptides to Induce Insulin Secretion inRodents

Ingested amino acids have been shown to have the capacity to induceinsulin secretion (Gannon M. C, and F. Q. 2010. Nuttall. Amino AcidIngestion and Glucose Metabolism—A Review. IUBMB Life, 62(9): 660-668).Protein ingestion increases plasma insulin significantly in comparisonto ingestion of glucose alone (Nuttall, et al. 1984. Effect of proteiningestion on the glucose and insulin response to a standardized oralglucose load. Diabetes Care. 7(5):465-470). Ingested protein increasesinsulin secretion in part via the action of incretin hormones, i.e.,glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropicpeptide (GIP), which are secreted by endocrine cells upon luminalexposure to nutrients (Baggio LL & DJ Drucker. 2007. Biology ofincretins: GLP-1 and GIP. Gastroenterology. 132:2131-2157). Amino acidssuch as leucine and arginine have also been shown to directly stimulateinsulin release (Newsholme P. et al. New insights into amino acidmetabolism, B-cell function and diabetes. Clin. Sci. (2005) 108:185-194). In these studies, the insulin response after acute dosing ofvarious nutritive proteins was measured in rodents.

Animals were treated and acutely dosed with various test articles aspart of pharmacokinetic rodent experiments according to methodsdescribed herein. Unless otherwise stated all dosing was at 2.85 g/kgbody weight. All treatment groups except for SEQID-00240 which had n=5rats, and SEQID-00587 which had n=3, contained n=4 rats.

Quantification of Plasma Insulin Using AlphaLISA® Insulin Immunoassay

Plasma Samples were Thawed on Ice and Centrifuged for 10 Minutes at1109×g to pellet insoluble material. AlphaLISA® Insulin Immunoassay Kit(PerkinElmer, AL204C) was removed from 4° C. cold room and kept on iceduring assay set up. 1× Assay Buffer was prepared by diluting 10× AssayBuffer with milliQ water.

Standard buffer for dilution of insulin was prepared at 25.9% fasted ratplasma in 1× Assay Buffer and used to prepare a 16 point standard curve.Plasma samples were prepared by diluting 7:20 in 1× Assay Buffer in a96-well PCR microplate.

Acceptor head mix was prepared by diluting Acceptor Beads andBiotinylated Anti-Insulin Antibody 1/400 in 1× Assay Buffer. Acceptorbead mix was pipetted, 20 μL/well, into a white opaque 384 wellmicroplate (PerkinElmer, OptiPlate-384), to this mixture was added 10μL/well of insulin standard in fasted rat plasma or sample rat plasma induplicate. The plate was sealed with a foil plate seal and incubated ona horizontal shaker at ˜600 rpm for 60 minutes at room temperature.

It was necessary to protect the Streptavidin Coated Donor Beads fromlight; as such, in a darkened room, donor bead mix was prepared bydiluting the streptavidin coated donor beads 1/125 in 1× Assay Buffer.After the first incubation step, 20 μL/well donor head mix was added tothe standard and samples. The assay plate was sealed and returned to thehorizontal shaker at ˜600 rpm, for 30 minutes at room temperature.Following the donor bead incubation, luminescence was read on theEnSpire Alpha plate reader.

Data were analyzed with Microsoft Excel version 14.0.7128.5000 (32-bit)and GraphPad Prism version 6.03. A standard curve was generated tolog(Insulin (IU)). Rat plasma insulin concentrations were interpolatedusing a sigmoidal, four parameter logistic equation. The mean ofduplicate concentration of insulin in the technical replicates for eachrat were plotted against time. Area under curve was integrated for 0-240minutes and 0-60 minutes using the Linear-Log Linear Method in MicrosoftExcel.

Quantification of Plasma Insulin Using a Rat Insulin Enzyme LinkedImmunosorbent Assay (ELISA).

An Ultra-Sensitive Rat Insulin ELISA Kit was obtained from Crystal Chem,Inc. (Catalog number 90060, Downers Grove, Ill.). Plates were washedusing a BioTek ELx50 microplate strip washer (BioTek, Winooski, Vt.).Absorbance was read on a Synergy Mx monochromator-based microplatereader (BioTek, Winooski, Vt.). Data was analyzed using Microsoft Excelversion 14.0.7128.5000 (Microsoft Corporation, Redmond, Wash.) andGraphPad Prism version 6.03 for Windows (GraphPad Software, La Jolla,Calif.).

The ELISA kit was pre-warmed to room temperature for 30 minutes prior tobeginning the assay set up. The standard curve dilutions were preparedin accordance with the manufacturer's instructions for running the assayin Wide Range format.

Plasma matrix from the naïve group and sample plasma were thawed on iceand then centrifuged at approximately 1000×rcf for 10 minutes at 4° C.to pellet any insoluble material.

Matrix Assay Buffer for running the insulin standard was prepared usingplasma matrix from the naïve group to a concentration of 5.26% in 95 μL.95 μL of Assay Buffer was added to all sample wells, and 95 μL of MatrixAssay Buffer was added to all standard wells. 5 μL of each sample andstandard were added in duplicate. The plates were incubated at 4° C. for2 hours. The plates were then washed five times with 300 μL/well 1× WashBuffer. The plates were tapped sharply several times on paper towels toremove any residual wash buffer.

Anti-Insulin Enzyme Conjugate Working Solution was prepared by combining2 volumes Anti-Insulin Enzyme Conjugate Stock with 1 volume EnymeConjugate Diluent, and mixing by pipetting up and down and gentlyvortexing. 100 μL/well of Anti-Insulin Enzyme Conjugate Working Solutionwas added to all wells. The plates were sealed and incubated at roomtemperature for 30 minutes and then washed seven times with 300 μL/well1× Wash Buffer. The plates were tapped sharply several times on papertowels to remove any residual wash buffer. 100 μL/well Enzyme SubstrateSolution was then added to each well and incubated in the dark at roomtemperature for 40 minutes. 100 μL/well Stop Solution was added to allwells. The absorbance was read on the Synergy Mx plate reader at 450 nmand 630 nm. Final values obtained were the A450 nm-A630 nm values.

The insulin standard curve was corrected for matrix concentration ofinsulin by subtracting the mean of the 0 ng/mL insulin standard fromeach of the standard well A_(450nm)-A_(630nm) values in Excel. Duplicatesample concentrations were determined by non-linear regression using a 4parameter logistic model of the background corrected standard followingan x=log(x) transformation of insulin concentration in GraphPad Prism 6.ANOVA and multiple comparison tests were conducted on GraphPad Prism 6.Area under curve was integrated for 0-240 minutes and 0-60 minutes usingthe Linear-Log Linear Method in Microsoft Excel.

In Vivo Plasma Insulin Concentrations

FIGS. 19 and 20 show the combined biological replicate data for a studyof vehicle and SEQID-00105 administered at three different doses andSEQID-00426, SEQID-00338, SEQID-00341 administered at one dose, whereplasma insulin was measured using the AlphaLISA Insulin kit. All errorbars represent the standard error of the mean. A one-way ANOVA withDunnett's multiple comparisons tests were used to compare within eachtreatment to time 0 and between treatments at the same time point tovehicle.

In FIG. 19, SEQID-00105 at 2.85 g/kg had a statistically significantincrease in plasma insulin concentration at 15, 30 and 60 minutesfollowing gavage (P<0.0001, P<0.0001, and P<0.05, respectively);SEQID-00105 at 1.78 g/kg had a statistically significant increase inplasma insulin concentration at 15 and 30 minutes following gavage(P=0.0005 and P<0.05, respectively); at the lowest SEQID-00105 doseplasma insulin concentration over the time course was not significantlydifferent from time 0. When compared to the plasma insulin concentrationof the vehicle control at each time point. SEQID-00105 at 2.85 g/kgshowed statistically significant greater plasma insulin than vehicle at15 minutes and 30 minutes following oral gavage (P<0.000 and P<0.001,respectively), SEQID-00105 at 1.78 g/kg showed a statisticallysignificant increase in plasma insulin concentration at 15 minutesfollowing oral gavage (P=0.0005). In FIG. 20, only SEQID-00338 had astatistically significant increase in plasma insulin concentration from0 at 15 and 30 minutes following oral gavage (P=0.005 and P<0.05,respectively). When compared to vehicle plasma insulin concentration ateach concentration SEQID-00338 was significantly greater than vehicle at15 minutes following oral gavage (P<0.01).

FIGS. 21 and 22 show the integrated area under curves for plasma insulinconcentrations measured for vehicle of SEQID-00105, SEQID-00426,SEQID-00338, SEQID-00341, error bars are the standard error of the mean.One-way ANOVA with Dunnett's multiple comparisons tests were used tocompare the AUCs to vehicle. SEQID-00105 at 2.85 g/kg had astatistically significantly greater plasma insulin AUC than vehicle whenintegrated from 0-240 minutes and 0-60 minutes (P=0.0005 and P<0.05,respectively).

FIGS. 23 and 24 show the combined biological replicate data for a studyof vehicle and SEQID-00423, SEQID-00587, SEQID-00105, SEQID-00424,SEQID-00425, and SEQID-00429, where plasma insulin was measured usingthe AlphaLISA Insulin kit. All error bars represent the standard errorof the mean. One-way ANOVA with Dunnett's multiple comparisons testswere used to compare within each treatment to time 0 and betweentreatments at the same time point to vehicle.

FIGS. 25 and 26 shows the integrated area under curves for plasmainsulin concentrations shown in FIGS. 23 and 24. One-way ANOVA withDunnett's multiple comparisons tests were used to compare the AUCs tovehicle. SEQID-00587 had a significantly greater plasma insulin AUC whenintegrated at 0-240 minutes (P<0.005).

FIG. 27 shows the combined biological replicate data for a study ofvehicle and SEQID-00105, SEQID-00240, and SEQID-00559, where plasmainsulin was measured using the Rat Insulin ELISA kit. All error barsrepresent the standard error of the mean. One-way ANOVA with Dunnett'smultiple comparisons tests were used to compare within each treatment totime 0, SEQID-00105, and SEQID-00559 both had a statisticallysignificant increase in plasma insulin concentration at 15 minutes postgavage compared to time 0 (P<0.05, both). SEQID-00240 had statisticallysignificant increase in plasma insulin at 15 and 30 minutes post gavagecompared to time 0 (P<0.05 & P<0.01, respectively). The vehicle had nostatistically significant change in plasma insulin concentrationcompared to time 0.

FIG. 28 shows the integrated area under curve from 0-240 and 0-60minutes post gavage for each treatment, error bars are the standarderror of the mean. No treatment showed a significantly greater AUCcompared to vehicle at 0-60 or 0-240 minutes by a Dunnett's multiplecomparisons test.

Example 25 Nutritive Polypeptide Stimulation of Glucagon Like Peptide 2Secretion in Healthy, Fasted Rats

Glucagon-like peptide-2 (GLP-2) is a thirty three amino acid peptideproduced by the post-translational cleavage of proglucagon. GLP-2 issecreted by the intestinal enteroendocrine L-cells of humans and rodentsalong with GLP-1 in response to exposure to nutrients in the gut lumen.GLP-2 has been shown previously to improve outcomes in the treatment ofshort bowel syndrome (Brinkman A S, Murali S G, Hitt S, Solverson P M,Hoist J J, Ney DM. 2012. Enteral nutrients potentiate glucagon-likepeptide-2 action and reduce dependence on parenteral nutrition in a ratmodel of human intestinal failure. Am. J. Physiol. Gastrointest. LiverPhysiol. 303(5):G610-G622) by supporting intestinal growth (Liu X,Murali S G, Hoist J J, Ney DM. 2008. Enteral nutrients potentiate theintestinotrophic action of glucagon-like peptide-2 in association withincreased insulin-like growth factor-I responses in rats. Am. J.Physiol. Gastrointest. Liver Physiol. 295(6):R1794-R1802).

Animals were treated and acutely dosed with test articles as part ofpharmacokinetic rodent experiments according to methods describedherein. In this experiment, two test articles were analyzed, vehicle anda nutritive formulation of SEQID-240, dosed at 1.54 g/kg.

Total GLP-2 Enzyme-Linked Immunosorbent Assay (ELISA)

Total GLP-2 was measured with Millipore Total GLP-2 ELISA Kit(Millipore, EZGLP2-37K). The ELISA kit was equilibrated to roomtemperature for a minimum of 30 minutes prior to running the assay. Thekit GLP-2 Standard, Quality Control 1 and Quality Control 2 werereconstituted with 500 μL MilliQ water, inverted 5 times and incubatedat room temperature for 5 minutes, then gently vortexed to mix. Thestandard curve was prepared by diluting the GLP-2 Standard serially 1:1in kit Assay Buffer to generate an eight point standard curve including0 ng/mL GLP-2. Plasma samples were thawed on ice and centrifuged for 10minutes at approximately 1109×rcf to pellet insoluble material. Fastedplasma matrix from untreated, fasted rat was prepared for running thestandard and quality controls in duplicate at 20% (2×).

1× Wash Buffer was prepared in a clean 500 mL glass bottle by combining50 mL 10× Wash Buffer with 450 mL MilliQ water. Strips were prepared bywashing 3 times with 300 μL 1× Wash Buffer applied with a 30-300 μL8-channel pipette. Between washes the wash buffer was decanted into awaste receptacle and the plate tapped sharply on a stack of paper towelsto remove remaining wash buffer.

Following the first wash. 90 μL of Assay Buffer was added to samplewells, and 50 μL of 20% matrix in Assay Buffer was added to all standardand quality control wells. 10 μL of sample was added to each sample welland 50 μL of standard and quality control were added to matrixcontaining wells. Samples, standards and quality control wells were runin duplicate, except for 0 ng/mL GLP-2 standard which was run inquadruplicate.

The plate was sealed with a plastic plate seal and incubated at roomtemperature on a horizontal plate shaker at 450 rpm for 2 hours.Following the first incubation, the plate was washed three times with 1×Wash Buffer, decanting into a waste receptacle and tapping the invertedplate sharply on a stack of paper towels to remove excess wash bufferafter each wash.

100 μL of Detection Antibody was added to each well and the plate wassealed with a plastic plate seal and incubated at room temperature on ahorizontal plate shaker at 450 rpm for 1 hour. Following the secondincubation, the plate was washed three times with 1× Wash Buffer,decanting into a waste receptacle and tapping the inverted plate sharplyon a stack of paper towels to remove excess wash buffer after each wash.

100 μL Enzyme Solution was added to each well and the plate was sealedwith a plastic plate seal and incubated at room temperature on ahorizontal plate shaker at 450 rpm for 30 minutes. Following the thirdincubation, the plate was washed three times with 1× Wash Buffer,decanting into a waste receptacle and tapping the inverted plate sharplyon a stack of paper towels to remove excess wash buffer after each wash.

100 μL Substrate was added to each well and the plate was sealed with aplastic plate seal and an opaque foil seal and incubated at roomtemperature on a horizontal plate shaker at 450 rpm for 20 minutes.Following substrate reaction, 100 μL of Stop Solution was added to eachwell and the plate gently shaken to mix.

Absorbance was measured on a SynergyMX Plate Reader at 450 nm and 590nm. Measured values were the difference between 450 nm and 590 nmabsorbance values.

Data were analyzed with GraphPad Prism 6.03. A standard curve wasgenerated to log(Total GLP-2 (ng/mL)) after subtracting the 0 ng/mLbackground value. Rat plasma GLP-2 concentrations were interpolatedusing a sigmoidal, four parameter logistic equation. The mean ofduplicate concentration of GLP-2 in the technical replicates for eachrat were plotted against time. The integrated area under curve wascalculated on Microsoft Excel where the area between each time point wascalculated for each biological replicate as the sum of the areas usingthe Linear-Log Trapezoidal Method.

FIG. 29 shows the calculated total GLP-2 concentration over a 4 hourtime course for SEQID-00240 and vehicle control. Vehicle GLP-2concentration did not change significantly at any of the time pointssampled compared to time 0, whereas SEQID-00240 showed a statisticallysignificant increase in GLP-2 concentration relative to time 0 at 15(P<0.00), 30 (P<0.0001) and 60 minutes (P<0.01) following SEQID-00240gavage (Dunnett's multiple comparison test). SEQID-00240 was compared tovehicle at each time point by ordinary One-Way ANOVA with a Dunnett'smultiple comparisons test post hoc analysis. GLP-2 concentration was notsignificantly different between treatments at time 0. GLP-2concentrations were statistically significantly greater than vehicle at15 (P<0.001), 30 (P<0.0001), 60 (P<0.0001) and 120 minutes (P<0.05)following treatment. These data show that an acute dose of SEQID-00240but not vehicle induces secretion of GLP-2 in healthy fasted rodents.

FIG. 30 shows the integrated GLP-2 area under the curve over the firsthour and the full 4 hours. The area under curve for GLP-2 wassignificantly greater in the SEQID-00240 treatment compared to vehiclewhen integrated over 0-60 minutes and over 0-240 minutes (P<0.005 &P<0.01, respectively, unpaired 2-tailed Student's t-test). This dataindicated that acute dosing of SEQID-00240 significantly stimulatedGLP-2 secretion in comparison to vehicle within the first hour of acutedosing in healthy fasted rodents.

Example 26 Effect of Orally Delivered Nutritive Polypeptides on PlasmaInsulin and Incretin Levels in Humans

The insulin and incretin response to protein ingestion is predicated onthe delivery of amino acids. The purpose of this study was to examinethe changes in plasma insulin concentrations in response to SEQID-00426and SEQID-00105 over a period of 240 minutes. Two groups of fourapparently healthy subjects between the ages of 18 and 50 received 20grams of the nutritive polypeptide formulations orally. All subjectswere fasted overnight (>8 hrs) before starting the study. Venous bloodsamples were collected at specified time points (i.e. 0, 15, 30, 60, 90,120, 150, 180, 210 and 240 minutes) following the oral ingestion ofnutritive polypeptide to assess changes in plasma insulin and incretinconcentrations. FIG. 31 shows the average insulin response of allsubjects to SEQID-00105, and FIG. 32 shows the average fold responseover baseline (time 0 min), measured as described herein. The error barson all figures correspond to the standard error of the mean. The firstphase insulin response occurs between time 0 min and 90 min. The secondphase insulin response occurs between 90 min and 210 min. A 1-way ANOVAcomparison across time indicates that there is a significant change inplasma insulin over time (p=0.003). A Dunnett multicomparison testindicates that the insulin values at 15 and 30 min time points aresignificantly different from that at time 0 min (p<0.05).

FIG. 33 shows the average insulin response of all patients toSEQID-00426, and FIG. 34 shows the average fold response over baseline(time 0 min), measured as described herein. The error bars on allfigures correspond to the standard error of the mean.

FIG. 35 shows the average total Gastric Inhibitory Polypeptide (GIP)response of all patients to SEQID-00426, and FIG. 36 shows the averagefold response over baseline (time 0 min), measured as described herein.The error bars on all figures correspond to the standard error of themean.

Example 27 In Vitro Demonstration of Skeletal Muscle Cell Growth andSignaling Using Nutritive Polypeptide Amino Acid Compositions ContainingTyrosine, Arginine, and/or Leucine

The mammalian target of rapamycin (mTOR) is a protein kinase an a keyregulator of cell growth, notably via protein synthesis, mTOR acts as amaster regulator of cellular metabolism that nucleates two complexes,mTORC1 and mTORC2 that have different kinase specificity and distinctprotein partners (citations from ESS-020).

mTOR drives protein synthesis across tissues, mTORC1 mediated responseto growth signaling is gated by amino acids. The localization of theresponse to lysosomes couples mTOR activation to muscle proteincatabolism, mTORC1 can be gated by essential amino acids (EAAs),leucine, and glutamine. Amino acids must be present for any upstreamsignal, including growth factors, to activate mTORC1 (citations fromESS-020).

These experiments demonstrated the capacity of arginine, tyrosine aswell as leucine to modulate mTORC1 activation by measuring downstreamphosphorylation of the ribosomal protein S6 (rps6) in response tostimulation by single amino acids in vitro.

Primary Rat Skeletal Muscle Cell (RSKMC) culture medium was purchasedfrom Cell Applications (Catalog number: R150-500, San Diego, Calif.).Starvation medium DMEM/F12 was bought from Sigma (Catalog number: D9785.St. Louis, Mo.). Customized starvation medium Mod.4 was purchased fromLife Technologies (Catalog number 12500062. Grand Island, N.Y.), whichdoes not contain any amino acids, phenol red, or glucose. Fetal bovineserum (FBS) and other growth factors were obtained from CellApplications (Catalog number: R151-GS, San Diego, Calif.). Tissueculture flasks and clear bottom 96-well tissue culture plates werepurchased from Corning Incorporated (Catalog number: 430641 and 353072,respectively, Corning, N.Y.). Trypsin/EDTA was obtained from LifeTechnology (Catalog number: 25200, Grand Island, N.Y.). DPBS and HBSSwere also purchased from Life Technologies (Catalog number: 14190,14175, respectively). AlphaScreen® SureFire® Ribosomal Protein S6 AssayKits was obtained from Perkin Elmer (Catalog number: TGRS6P2S10K).

Primary Rat Skeletal Muscle Cell (RSKMC) culture. RSKMC were isolatedusing protocol described herein and cryopreserved in liquid nitrogen.The cells were also maintained in RSKMC medium (Cell Applications) inT75 tissue flask in a 37° C., 5% CO2 tissue culture incubator (Model3110, Thermo Fisher Scientific). The cells were split every three daywhen they reached ˜90% confluency. RSKMC cells were cultured in RSKMCmedium in T75 tissue flask to 100% confluency. The culture medium wasaspirated from the culture flask and rinsed once with 10 ml of DPBS, andthen 1.5 ml of 0.25% trypsin/EDTA was added to the cells. After thecells were detached from the flask, 10 ml of culture medium were added.The medium was pipetted up and down with a 10 ml pipet to detach thecells from the flask. The cells were then seeded into clear bottom96-well tissue culture plates at a density of 50,000 cells per well.Following overnight culture in a 37° C., 5% CO2 incubator, the cellswere starved over a period of 4 hours with starvation DME/F12 mediumwithout FBS and leucine in a 37° C., 5% CO2 tissue culture incubator,then starved for another hour incubation with Hank's Buffered SaltSolution (HBSS). The cells were stimulated with different concentrationsof leucine in starvation medium for 15 and 30 minutes. The cells werealso treated with 5 nM of Rapamycin (R0395, Sigma) or 100 nM of Insulin(19278, Sigma) for 15 and 30 minutes. The cells were lysed in 20 μL ofLysis Buffer (Perkin Elmer) for 10 minutes at room temperature withshaking at 725 rpm. The cell lysates were stored at −80° C. andAlphaScreen® assay was performed the next day. AlphaScreen® SureFire®Ribosomal Protein S6 Assay was performed according to manufacturer'smanual.

FIG. 37 shows the relative alphascreen signal (y-axis) measured atdifferent Leucine concentrations, demonstrating that leucine stimulatesphorphorylation of rps6 in primary RSkMC in a dose-dependent manner.This stimulation was inhibited in a dose dependent manner by the mTORinhibitor, rapamycin.

FIG. 38 shows that leucine stimulates phosphorylation of rps6 in primaryRSkMC in a dose-dependent manner in both a complete amino acid medium(Arg, His, Lys, Asp, Glu, Ser, Thr, Asn, Gin, Cys, Gly, Pro, Ala Val,Ile, Met, Phe, Tyr, Trp), as well as a minimal 12 amino acid mixturecontaining only (Arg, His, Lys, Thr. Gin, Cys, Val, Ile, Met, Phe, Tyr,and Trp) at their DME/F12 concentrations (see table E27B).

Primary skeletal muscle cells obtained from the Soleus (Sol),gastroenemius (GS) and extensor digitorum longus (EDL) of twoSprague-Dawley rats. FIGS. 39, 40, and 41 shows that leucine stimulatesmTOR RPS6 pathway using isolated primary cells in a dose dependentmanner.

Arginine, tyrosine and leucine are required to fully stimulate the mTORpathway. Cells were starved as described above in Mod.4 medium withoutfetal bovine serum and then stimulated in Mod.4 medium lacking each ofthe respective single amino acids (see table E27A and E27B forcomposition of Mod.4 medium and DME/F12 amino acid levels,respectively).

TABLE E27A Vitamins μM Other mM Inorganic Salts mM Choline chloride 64.1D-Glucose 17.5 Calcium chloride, 1.05 (Dextrose) anhydrous D-Calcium 4.7Sodium Pyruvate 0.5 Copper (II) Sulfate 5.21E−06 pantothenatePentahydrate Folic Acid 6.01 HEPES 15 Magnesium Sulfate 0.407 (anhyd.)Niacinamide 16.56 Hypoxanthine 0.018 Magnesium Chloride 0.301 Pyrodoxine9.88 Linoleic Acid 1.50E−04 Potassium Chloride 4.157 hydrochlorideRiboflavin 0.58 Putrescine 5.03E−04 Sodium Bicarbonate 0.014Hydrochloride Thiamine 6.44 Thioctic Acid 5.10E−04 Sodium Chloride 120.6hydrochloride i-inositol 70 Thymidine 1.51E−03 Sodium Phosphate 0.521Monobasic D-biotin 1.43E−02 Phenol Red 5.00 × 10{circumflex over ( )}⁻⁴Sodium Phosphate 0.5 (%) Dibasic Vitamin B-12 0.5 Iron (III) Nitrate1.24E−04 Nonahydrate Iron (II) Sulfate 1.50E−03 Heptahydrate ZincSulfate 1.50E−03 heptahydrate

TABLE E27B Amino Acids μM Amino Acids μM Glycine 250 L-Leucine 451L-Alanine 50 L-Lysine 500 L-Arginine 700 L-Methionine 116 L-Asparagine57 L-Phenylalanine 215 L-Aspartic Acid 50 L-Proline 150 L-Cysteine 100L-Serine 250 L-Glutamic Acid 100 L-Threonine 449 L-Glutamine 2500L-Tryptophan 44 L-Histidine 150 L-Tyrosine 214 L-Isoleucine 416 L-Valine452

Primary muscle cells were starved for 2 hours, and then stimulated with0 μM or 500 μM single amino acid in 37 C, 5% CO2 tissue cultureincubator for 30 minutes. The treatment was performed in triplicate.FIG. 42 demonstrates that the combination of leucine, arginine, andtyrosine are necessary and sufficient to activate the mTOR pathway inRMSKC to the same degree as a full complement of all 20 amino acids attheir DME/F12 concentrations, and that none of the individual or pairedtreatments of Leu, Arg, or Tyr were capable of a similar response.

FIGS. 43, 44, and 45 show the effect of a dose response of each aminoacid (Leu, Arg, Tyr) in the background of all other 19 amino acids vsthe other 2 amino acids (e.g. dose response of Arg in a background ofTyr and Leu) on rps6 phosphorylation. These data indicate the synergybetween Leu, Arg, and Tyr is dose dependent. Comparing the 20 aminoacids response at low doses of Arg to that in a comparable high Leu andTyr background, there is a reduction in the degree of stimulation causedby the other 17 amino acids. At high doses of Arg, the response in bothbackgrounds equalizes. Comparing the 20 amino acids response at lowdoses of Leu to that in a comparable high Arg and Tyr background, thereis no difference in rps6 phosphorylation response. Comparing the 20amino acid response at low doses of Tyr to that in a comparable high Leuand Arg background, the other 17 amino acids can further potentiate themTOR response.

Example 28 Determination of Safety and Lack of Toxicity ofLeucine-Enriched Nutritive Polypeptides Following Oral Consumption byRodents

An acute toxicology study was completed to confirm the expected safetyof nutritive polypeptides SEQID-00105, SEQID-00363, and SEQID-00426 inrodents.

Each study group contained 5 male rats and 5 female rats (10 Wistar, 6-7weeks old, Males 220-250 g, Females 180-200 g). Test formulations were350 g/L nutritive polypeptide and aqueous buffer as a control. Animalswere acclimated for 1 week upon arrival and given a diet of regular chowalways available. Before dosing, animals were weighed and pre-bleedswere taken. Single dosage of 10 ml/kg was completed via oral gavage. Ondays 2, 6 and 7, body and food weights were taken. On day 6 animals werebled in EDTA and Sodium Heparin tubes. On day 7 weights were taken andanimals were euthanized followed by immediate necropsies. Eight organs(heart, liver, lung, spleen, kidney, brain, bladder, and smallintestine) were removed, weighed and stored in 10% formaldehyde. Duringthe study clinical observations for signs of stress, pain, and abnormalactivity were performed daily.

For all three tested nutritive polypeptides the protein and buffer werewell tolerated as no abnormalities were seen in the animals. Allactivity from the animals was normal and no other signs of pain ordistress were observed.

Example 29 Analytical Demonstration of Nutritive PolypeptideDigestibility

The digestion of nutritive polypeptides was analyzed via in vitrosimulated digestion assays. In vitro digestion systems are used tosimulate the breakdown of polypeptides into bioaccessible peptides andamino acids, as occurs in vivo while passing through the stomach andintestine (Kopf-Bolanz, K. A. et al., The Journal of nutrition 2012;142: 245-250, Hur, S. J. et al., Food Chemistry 2011; 125: 1-12).Simulated gastrointestinal digestion is also predictive of potentialprotein allergenicity, since digestion-resistant polypeptides may beabsorbed and cause sensitization (Astwood et al., Nature Biotechnology1996; 14: 1269-1273).

Nutritive Polypeptide Half-Life During Simulated Digestion.

One metric for quantifying the breakdown of polypeptides from an intactform to smaller peptides is the intact half-life. In this experiment thenutritive polypeptide was exposed to a series of proteases that areactive in the stomach (pepsin) and intestine (trypsin and chymotrypsin),and the presence of intact protein was measured over time. Specifically,the nutritive polypeptide was first treated at a concentration of 2 g/Lwith simulated gastric fluid (SGF) (0.03 M NaCl, titrated with HCl to pH1.5 with a final pepsin:polypeptide ratio of 1:20 w/w) at 37°. Timepoints were sampled from the reaction and quenched by addition of 0.2 MNa2CO3. After 120 min in SGF, the remaining reaction was mixed 50:50with simulated intestinal fluid (SIF) (18.4 mM CaCl2, 50 mM MES pH 6.5with a final trypsin:chymotrypsin:substrate ratio of 1:4:400 w/w) andneutralized with NaOH to pH 6.5. Time points were sampled from thereaction and quenched by addition of Trypsin/Chymotrypsin Inhibitor(Sigma) solution until 240 min.

Time point samples were analyzed for intact protein by chipelectrophoresis, polyacrylamide gel electrophoresis, or western blot.For chip electrophoresis (Labchip (GX II), samples were analyzed using aHT Low MW Protein Express LabChip® Kit (following the manufacturer'sprotocol). A protein ladder was loaded every 12 samples for molecularweight determination (kDa) and quantification. For polyacrylamide gelelectrophoresis, samples (1 μg) were separated on a NuPAGE® Novex®Bis-Tris Precast gel (Life Technologies) according to the manufacturer'sprotocol. The gel was stained using SimplyBlue™ SafeStain (Invitrogen)and imaged using a Chemidoc XRS+(BioRad) or transferred ontonitrocellulose membranes using the iBlot® Dry Blotting System (LifeTechnologies) and iBlot® Western Detection Kit (Life Technologies)according to the manufacturer's protocol. Proteins were detected byblotting with Anti-His [C-term]-HRP antibody diluted 3:5000 in Blok™-POBlocking Buffer using the SNAP I.d.® Protein Detection System(Millipore) according to the manufacturer's protocol. Blots were treatedwith Luminata Classico Western HRP Substrate (Millipore) according tothe manufacturer's protocol and imaged using chemiluminescent detectionon the Molecular Imager® Gel Doc™ XR+ System (Bio-Rad). Quantificationof intact protein was determined by densitometry using ImageLab(BioRad). For all analysis methods the relative concentration of thepolypeptide at each time point (if detected) was plotted overtime andfit to an exponential curve to calculate the intact half-life.

Alternatively, samples were analyzed by determining the percentage ofintact protein remaining at a single time point (eg, half-life less than2 min). Specifically, the t=0 (enzyme-free control) and t=2 min samplesfrom the SGF digest were analyzed for intact protein as described bychip electrophoresis, SDS-PAGE, western blot, and/or LC-MS/MS. Relativequantities of polypeptides at each time point were determined and thepercentage of intact protein remaining at t=2 was determined. Intacthalf-life values determined using this method are reported as greater orless than 2 min to indicate more or less than 50% of the proteinremained intact at t=2 min, respectively. Results for intact SGFhalf-life determined by either method are reported in Table E29A.

TABLE E29A Intact half-lives calculated from in vitro intact proteindetection during SGF treatment. SGF Half-life (t½) in min SEQID-00001 5SEQID-00001 (HEK293) 8.6 SEQID-00008 0.9 SEQID-00009 3 SEQID-00076 0.3SEQID-00085 0.9 SEQID-00087 0.3 SEQID-00098 0.4 SEQID-00099 1SEQID-00100 2 SEQID-00102 0.6 SEQID-00103 0.3 SEQID-00103 (HEK293) <2SEQID-00104 0.3 SEQID-00105 0.2 SEQID-00105 (BS) 0.5 SEQID-00105(HEK293) <2 SEQID-00143 0.3 SEQID-00212 0.3 SEQID-00215 2 SEQID-00218 6SEQID-00220 0.5 SEQID-00226 0.7 SEQID-00236 10 SEQID-00237 0.6SEQID-00240 0.7 SEQID-00241 0.3 SEQID-00265 29 SEQID-00269 41SEQID-00284 1 SEQID-00287 3 SEQID-00298 (AN) 0.3 SEQID-00298 (BS) 0.1SEQID-00302 0.2 SEQID-00305 0.2 SEQID-00338 0.2 SEQID-00338 (BS) 0.2SEQID-00341 0.2 SEQID-00343 0.3 SEQID-00345 0.8 SEQID-00346 0.2SEQID-00352 0.2 SEQID-00354 0.2 SEQID-00356 0.2 SEQID-00357 0.2SEQID-00359 0.2 SEQID-00363 20 SEQID-00363 (E. coli) <10 SEQID-00407(BS) 0.2 SEQID-00417 0.2 SEQID-00418 0.2 SEQID-00418 (E. coli) 0.5SEQID-00420 1.2 SEQID-00423 (BA) 0.3 SEQID-00423 (BA) 3 SEQID-00424 (AO)0.2 SEQID-00424 (AO) 0.6 SEQID-00425 (KL) 0.3 SEQID-00426 (TL) 0.3SEQID-00429 (BL) 5 SEQID-00485 0.5 SEQID-00502 0.6 SEQID-00510 0.3SEQID-00511 0.3 SEQID-00546 <10 SEQID-00559 0.5 SEQID-00587 2.4SEQID-00598 0.5 SEQID-00601 0.2 SEQID-00605 0.2 SEQID-00606 0.3SEQID-00610 0.4 SEQID-00622 6.6 SEQID-00647 0.2 SEQID-00672 (BS) 0.3SEQID-00678 (BS) 0.2 SEQID-00690 (BS) 4.4 All proteins were produced inE. coli, unless otherwise noted. AN = Aspergillus niger, AO =Aspergillus oryzae, BS = Bacillus subtilis, BA = Bacillusamyloliquefaciens, KL = Kluyveromyces lactis, TL = Thermomyceslanuginosus, BL = Bacillus lichenifomis. Alpha-mannosidase- treatedSEQID-00363 and protein proteins originating from AO, BA, KL, TL, and BLwere produced as described herein.

Nutritive Polypeptide Release of Amino Acids During Simulated Digestion.

An additional method of quantifying polypeptide digestion is to measurethe amount of free amino acids present after exposure to a simulateddigestive system. In this method, pancreatin, a mixture of enzymes, isused to simulate intestinal proteases. Specifically, the digestion ofpolypeptides into amino acids was analyzed by an in vitroPancreatin-based digestion assay followed by free amino acid analysisusing reversed phase HPLC (RP-HPLC). The nutritive polypeptide was addedto SGF (0.92 g/L Pepsin (Sigma), 0.03 M NaCl titrated with HCl to pH1.5) at a final concentration of 4 g/L and incubated at 37° C. for 120min. After 120 min. Na2CO3 was added to a final concentration of 16 mMto quench the pepsin reaction. The resulting reaction was mixed 50:50with 2× concentrated SIF (0.78 mg/ml Porcine Pancreatin (Sigma), 18.4 mMCaCl2, 50 mM MES pH 6.5) and incubated for 240 min. Time points weresampled from the reaction and quenched by heating to 95° C. for 5 min.Control samples were protease-free.

Time points were analyzed for free amino acids using RP-HPLC amino acidanalysis as described in Henderson, J. W., et al. Agilent Technologies(2010). Analyses were performed using an Agilent 1100 series system.Primary amino acids were derivatized pre-column at room temperature,online, using o-phthalaldehyde (OPA). The OPA-derivatives were separatedusing the Zorbax Eclipse-AAA 4.6×150 mm, 3.5 μm column at 40° C. Theseparation gradient transitioned from 100% 40 mM Na2HPO4 pH 7.8 to 65%acetonitrile/methanol/water mixture (45/45/10) over 23 minutes. Analyteswere detected by fluorescence at 340 nm Ex/450 nm Em. FIG. 46demonstrates a representative time-course of free Leu concentrationduring a Pancreatin digest of SEQID-00105. Free Leu concentrations forsamples at the 120 min time point of the Pancreatin digest aresummarized in Table E29B.

TABLE E29B Free Leu detected at 120 min time point of Pancreatin digestof nutritive polypeptides. Free Leu (μM) at 120 min time point ofPancreatin digest SEQID-00076 824.3 SEQID-00103 793.8 SEQID-00105 1357.6SEQID-00298 (BS) 1030.8 SEQID-00338 1181.7 SEQID-00341 1143.5SEQID-00352 906.1 SEQID-00363 511 SEQID-00363 561.5 SEQID-00423 587.1SEQID-00424 758.7 SEQID-00425 713.1 SEQID-00426 952.3 SEQID-00426 955.2SEQID-00429 580.7 SEQID-00485 764.9 SEQID-00605 937.1

Nutritive polypeptide release of peptides during simulated digestion.Samples from the simulated Pancreatin-based in vitro digestion describedherein were analyzed for peptides by LC-MSIMS. To prepare the samplesfor LC-MS/MS analysis, the sample pH was adjusted to pH 3 withtrifluoroacetic acid (TFA) and peptides were extracted usingHydrophilic-lipophilic Balance (HLB) solid phase extraction cartridges(Waters). Cartridges were activated with 2 mL of acetonitrile andequilibrated with 2 mL of 0.1% TFA. Samples were loaded and cartridgeswashed with 2 mL 0.1% TFA and eluted with 1 mL of 70% acetonitrile/0.1%TFA. The eluted peptides were dried to completion and reconstituted in50 μL 0.1% TFA. The eluted peptides (4 μL) were loaded on-column andanalyzed by nano LC-MS/MS with a Waters NanoAcquity HPLC systeminterfaced to a ThermoFisher Orbitrap Velos Pro. Peptides were loaded ona trapping column and eluted over a 75 μm analytical column at 350nL/min; both columns were packed with Jupiter Proteo resin (Phenomenex).A 1 h gradient was employed. The mass spectrometer was operated indata-dependent mode, with MS performed in the Orbitrap mass analyzer at60,000 FWHM resolution and MS/MS performed in the LTQ linear ion trapmass spectrometer. The fifteen most abundant ions were selected forMS/MS. Data were searched against an appropriate database using Mascotto identify peptides. Mascot DAT files were parsed into the Scaffoldsoftware for validation, filtering and to create a nonredundant list persample. Data were filtered using a minimum protein value of 95% and aminimum peptide value of 50%.

Unique peptides were detected at the 240 min time point of thePancreatin digest by LC-MS/MS after in vitro digestion of a given SEQID.Unique peptides detected for the SEQID-00105 sample were: LFDKDNNGSIS,FDKDNNGS, FDKDNNGSIS/FDKDNnGSIS, FDKDNNGSISS, FDKDNNGSISSSEL, DKDNNGSI,DKDNNGSIS, SLGLSPSE, NEIDVDCIN, IDVDGNH, IDVDCiNHQ,IDVDGNHQIE/IDVDGNHQIE, KVFDKNGDG, VFDKNGDGLIS, DKNGDGL, KLTDAEV,LREVSDGSGEINIQQF, REVSDGSG, REVSDGSGE, REVSDGSGEI,REVSDGSGiEIN/REVSDCISGEIN, REVSDIXSGEINIQ, REVSDGSGEINIQQF, EVSDGSGEI,EVSDGSGEIN. Unique peptides detected for the SEQID-00426 sample were:YSFEDSGVGDVT, YSFEDSGVGDVTG, SFEDSGVGDVTG, FEDSGVGDV, EDSGVGDVT,EDSGVGDVTG, EDSGVGDVTGF, DSGVGDVT, LRGnGYD, LRGnGYDIDV, ITHTNDIVPR,HTNDIVPR, TNDIVPR, NDIVPR, YSHSSPE, DIVKIEGIDATGGNNQPNIPDIPAHL, KIEGID,KIEGIDATGGNNQPNIPDIPA, IEGIDATGGNNQPNIPDIPA, EGIDATGGNNQPNIPDIPA,GIDATGGNNQPNIPDIPA, IDATGGNNQPNIPD, IDATGGNNQPNIPDIP, IDATGGNNQPNIPDIPA,IDATGGNNQPnIPDIPA, IDATGGNNQPNIPDIPAH,DATGGNNQPNIPDIPA/DATGGNNPAqPNIPDIPA, ATGGNNQPNIPD, ATGGNNQPNIPDIP,ATGGNNQPNIPDIPA/ATGGNNqPNIPDIPA, ATGGNNQPNIPDIPAH, TGGNNQPNIPDIPA,CGNNQPNIPDIP/GGNnQPNIPDIP, GGNNQPNIPDIPA/GGnNQPNIPDIPA/GGnnQPNIPDIPA,GNNQPNIPDIPA/GNNqPNIPDIPA, NNQPNIPDIPA, NQPNIPDIPA, PNIPDIPA.

Nutritive Polypeptide Intact Half-Life Determination in a ComplexMixture.

The in vitro intact half-life of multiple polypeptides in a complexmixture was determined using the simulated gastric in vitro digestiondescribed above. Briefly, the 168 nutritive polypeptide library wasgenerated as described herein by cloning, transforming, and expressing agene library encoding 168 proteins as a single mixture. Therecombinantly expressed proteins were purified from host cell proteinsby IMAC purification as described herein.

The 168 Protein Library was treated with SGF as described above and thet=0 and t=10 min samples were analyzed for intact protein by LC-MS/MS.To begin, 10 μg of sample was loaded onto a 10% SDS-PAGE gel(Invitrogen) and run approximately 5 cm into the gel. The gel wasexcised into ten fractions from 100 kD to the dye front and the gelslices were processed by washing with 25 mM ammonium bicarbonate,followed by acetonitrile. Gel fractions were then reduced with 10 mMdithiothreitol at 60° C., followed by alkylation with 50 mMiodoacetamide at room temperature. Finally, the samples were digestedwith trypsin (Promega) at 37° C. for 4 h and the digestions werequenched with the addition of formic acid. The samples were thenanalyzed by nano LC/MS/MS using an EasynLC 1000 HPLC system interfacedto a ThermoFisher Q Exactive. Peptides were loaded on a trapping columnand eluted over a 75 μm analytical column at 350 nL/min; both columnswere packed with PepMap C18 3 μm resin (ThemoFisher). A 1 hour gradientwas employed. The mass spectrometer was operated in data-dependent mode,with MS and MS/MS performed in the Orbitrap at 70,000 FWHM resolutionand 17,500 FWHM resolution, respectively. The fifteen most abundant ionswere selected for MS/MS. Data were searched against an appropriatedatabase using Mascot to identify peptides. Mascot DAT files were parsedinto the Scaffold software for validation, filtering and to create anonredundant list per sample. Data were filtered at 1% protein andpeptide false discovery rate (FDR) and requiring at least two uniquepeptides per protein. A full list of detected proteins and theirspectral counts (SpC) was generated and reported as a function of eachcollected gel fraction. SpC are a count of the number of spectraidentified for a given protein and are used as a measure of relativeprotein abundance (Liu, H. et al., Analytical Chemistry 2004, 76:4193-4201). To calculate the percentage of intact protein remaining atthe 10 min time point of the SGF digest the number of SpC representativeof intact peptide in the t=10 min sample were divided by the number ofSpC representative of intact peptide in the t=0 min sample. The numberof SpC representative of intact peptide was defined as the sum of theSpC in the fraction with the highest number of SpC assigned to thatprotein in the t=0 min sample and the two flanking fractions. Resultsfor % Intact Protein at 10 min are shown in Table E20C. Intact half-lifevalues for purified proteins, determined by chip electrophoresis, andpercentage of intact peptide remaining at 10 min for proteins detectedin the 168 SEQID Library, determined by LC-MS/MS analysis, are comparedfor fourteen polypeptides in Table E20D. The linear relationship betweenpercentage protein remaining intact at t=10 min and half-life value wasanalyzed and the R2 value determined to be 0.72.

TABLE E20C Percent intact protein remaining at 10 min time point of 168nutritive polypeptide library SGF digest. % intact Protein at Protein 10min SEQID-00338 3.9 SEQID-00484 0 SEQID-00485 0 SEQID-00489 0SEQID-00495 0 SEQID-00496 0 SEQID-00497 20.3 SEQID-00502 9.7 SEQID-005070 SEQID-00509 36.4 SEQID-00510 13.4 SEQID-00511 4.3 SEQID-00515 17SEQID-00518 0 SEQID-00520 0 SEQID-00521 11.5 SEQID-00524 0 SEQID-0052513.7 SEQID-00528 11.8 SEQID-00529 0 SEQID-00532 0 SEQID-00533 19SEQID-00534 0 SEQID-00536 11.8 SEQID-00540 0 SEQID-00541 0 SEQID-00544 0SEQID-00545 0 SEQID-00546 0 SEQID-00552 79 SEQID-00555 6.8 SEQID-005593.1 SEQID-00562 0 SEQID-00564 89.6 SEQID-00570 91.4 SEQID-00573 66.7SEQID-00574 0 SEQID-00577 30.8 SEQID-00581 33.3 SEQID-00582 15.2SEQID-00583 0 SEQID-00587 21.7 SEQID-00590 0 SEQID-00591 20 SEQID-0059224.3 SEQID-00598 24.3 SEQID-00599 0 SEQID-00601 1.1 SEQID-00602 0SEQID-00603 0 SEQID-00605 0 SEQID-00606 0 SEQID-00607 0 SEQID-00609 0SEQID-00610 3.3 SEQID-00612 0 SEQID-00613 0 SEQID-00615 85.7 SEQID-0061743.9 SEQID-00618 0 SEQID-00619 68.5 SEQID-00620 0 SEQID-00622 43.6SEQID-00623 63.6 SEQID-00624 0 SEQID-00625 0 SEQID-00626 0 SEQID-00628 0SEQID-00629 40 SEQID-00631 17.1 SEQID-00632 1.2 SEQID-00633 92.1SEQID-00634 36.8 SEQID-00636 60 SEQID-00638 0 SEQID-00639 0 SEQID-0064050 SEQID-00641 21.2 SEQID-00642 75 SEQID-00643 13.6 SEQID-00644 0SEQID-00645 0 SEQID-00647 12 SEQID-00648 39.5

TABLE E20D Comparison of intact half-life values for purified proteins,determined by chip electrophoresis, and percentage of intact peptideremaining at 10 min for proteins detected in the 168 nutritivepolypeptide library, determined by LC-MS/MS analysis. Half-life Protein(min) % Remaining at 10 min SEQID-00338 0.2 3.9 SEQID-00601 0.2 1.1SEQID-00605 0.2 0 SEQID-00647 0.2 12 SEQID-00510 0.3 13.4 SEQID-005110.3 4.3 SEQID-00606 0.3 0 SEQID-00610 0.4 3.3 SEQID-00559 0.5 3.1SEQID-00485 0.5 0 SEQID-00598 0.5 24.3 SEQID-00502 0.6 9.7 SEQID-005872.4 21.7 SEQID-00622 6.6 43.6

Example 30 Viscosity of Nutritive Polypeptides

It has been demonstrated that the presence of strong attractiveself-associating interactions results in higher viscosity solutions(Yadav, Sandeep, et al. Journal of pharmaceutical sciences 99.12 (2010):4812-4829.). Specifically, electrostatic interactions of oppositelycharged residues results in high viscosity solutions (Liu, Jun, et al.Journal of pharmaceutical sciences 94.9 (2005): 1928-1940.). A nutritivepolypeptide with low viscosity can be selected using net charge orcharge per amino acid calculations described herein, and selectingproteins with highly positive or highly negative charges. Proteinsselected in this way would lack complementary electrostatic interactionsand would instead have an overall repulsive force that limits theability to self-associate thus reducing viscosity of the solutions.

Solutions of a nutritive polypeptide (SEQID-00105) and whey weremeasured for relative viscosity. Both proteins were resuspended withwater to the desired concentration for analysis. Viscosity was measuredusing a Brookfield LVDV-II+ PRO Cone/Plate with a CPE-40 spindle. Alltests were performed at 4 C and 25 C. Sample volume was 0.5 ml.Temperature was maintained with a Brookfield TC-550AP-115 ProgrammableTemperature Bath. All samples were equilibrated for a minimum of twominutes at 4 C and one minute at 25 C. All readings were taken between10% and 100% torque. FIG. 47 shows viscosity measured in centipoise forSEQID-00105 at 4 C (closed circles) and 25 C (open circles) and whey at4 C (closed squares) and 25 C (open squares).

SEQID-00105 has been shown herein to have a negative net charge across arange of pH, and SEQID-00105 is presently shown at multiple temperaturesand polypeptide concentrations to be less viscous than whey, which is adisperse mixture of proteins without a dominant single charge.

To generate a solution with increased viscosity transglutaminase can beused to create a network consisting of enzyme-induced permanent covalentcross-links between nutritive polypeptides thereby generatingadditionally viscous solutions. This enzyme treatment can also befollowed by thermal processing to make a viscous solution containing anutritive polypeptide. To generate nutritive polypeptide samplescontaining crosslinks that increase viscosity, a sample is mixed with atransglutaminase solution at pH 7.0 to give an enzyme to protein weightratio of 1:25. The enzyme-catalyzed cross-linking reaction is conductedat 40° C. in most of the experiments.

Example 31 Analytical Demonstration of Nutritive Polypeptide Solubilityand Thermostability

Solubility. The solubility of proteins was evaluated by determining theprotein concentration of reconstituted lyophilized powder, centrifugalfiltered, and/or ultrafiltered solutions (Carpenter et al. (2002)Rational Design of Stable Lyopholized Protein Formulations: Theorty andPractice, Kluwer Academic/Plenum publishers, New York, pp. 109-133;Millipore publication, Amicon Ultra: Centrifugal Filter Devices for theConcentration and Purification of Biological Samples (2001); Oss et al.(1969) A membrane for the rapid concentration of dilute protein samplesin an ultrafilter. Clinical Chemistry, 15(8): 699-707). Protein sampleswere dried by lyophilization on a FreeZone Freeze Dry System (Labconco)using the manufacturer's standard protocol and then resuspended inbuffer to the desired concentration. Centrifugal and tangentialultrafiltration were used to selectively remove buffer from the proteinsample until the desired concentration was reached. Centrifugalultrafiltration of protein solutions was performed by centrifugation(10,000×g) of 10 mg of protein in an Amicon centrifugal filter(Millipore) with a molecular weight cutoff of 3 kDa, 10 kDa, or 30 kDa,depending on the protein size, until the desired concentration wasreached. Ultrafiltration of protein solutions was performed on Hydrosartultrafiltration cassettes (Sartorius Stedim, Bohemia, N.Y.) with amolecular weight cutoff of 3 kDa, 10 kDa, or 30 kDa, depending on theprotein size, at a cross flow rate of 12 L/m2/min. For most processes,transmembrane pressure was maintained at 20 psi and performed until thedesired concentration was reached.

The protein concentration of the above samples was measured by one or acombination of the following methods: Coomassie Plus Protein Assay,absorbance at 280 nm (A280), and total amino acid analysis. CoomassiePlus Protein Assays (Pierce) were performed according to themanufacturer's protocol. Absorbance at 280 nm was measured on a Nanodrop2000 UV-Vis spectrophotometer. Protein concentration was determinedusing the A280 value and molar extinction coefficient, which wascalculated by primary amino acid sequence using ProtParam (Gasteiger,Elisabeth, et al. The proteomics protocols handbook. Humana Press, 2005,571-607.). Total amino acids were analyzed by HPLC after acid hydrolysisas described in Henderson, J. W., et al. Agilent Technologies (2010).

TABLE E31A Solubility of proteins. Protein Solubility (g/L) SEQID-00008265 SEQID-00009 53 SEQID-00076 150 SEQID-00085 50 SEQID-00087 176SEQID-00099 91 SEQID-00100 107 SEQID-00102 120 SEQID-00103 133SEQID-00104 192 SEQID-00105 500 SEQID-00115 70 SEQID-00220 166SEQID-00226 107 SEQID-00236 60 SEQID-00240 163 SEQID-00241 207SEQID-00265 95 SEQID-00269 159 SEQID-00287 192 SEQID-00298 (BS) 209SEQID-00302 158 SEQID-00305 231 SEQID-00338 254 SEQID-00341 166SEQID-00345 196 SEQID-00346 161 SEQID-00352 223 SEQID-00354 235SEQID-00357 211 SEQID-00363 (AN) 336 SEQID-00363 229 a-mannosidasetreated SEQID-00423 (BA) 193 SEQID-00424 (AO) 205 SEQID-00425 (KL) 190SEQID-00426 (TL) 138 SEQID-00429 (BL) 214 SEQID-00485 99 SEQID-00510 135SEQID-00511 135 SEQID-00546 149 SEQID-00559 156 SEQID-00587 223SEQID-00598 150 SEQID-00605 128 All proteins were produced in E. coli,unless otherwise noted. AN = Aspergillus niger, AO = Aspergillus oryzae,BS = Bacillus subtilis, BA = Bacillus amyloliquefaciens, KL =Kluyveromyces lactis, TL = Thermomyces lanuginosus, BL = Bacilluslicheniformis. Alpha-mannosidase-treated SEQID-00363 and protein andoriginating from AO, BA, KL, TL, and BL were produced as describedherein.

pH Solubility. The pH solubility of proteins was determined in a buffercocktail of Citric Acid and Dibasic Sodium Phosphate over a pH range of2.8 to 7.1, pH solutions were prepared as outlined in Table E31B.Protein was either lyophilized and then resuspended in buffer cocktailmixtures, or concentrated and then spiked into buffer cocktail mixturesat a final protein concentration of 5 to 30 mg/ml. As a control, proteinwas also dissolved in a solution of 8 M urea. Protein solutions wereshaken for 10 min at room temperature. Turbidity of proteins wasdetermined by measuring the absorbance of protein solutions at 650 nm.The protein solution was then centrifuged for 10 min at 1100×g to pelletundissolved or precipitated protein. The soluble protein fraction(supernatant) was sampled and protein concentration was measured by oneor more of the following methods: Coomassie Plus Protein Assay (Pierce).Chip electrophoresis, gel electrophoresis, and/or absorbance at 280 nm.The pH range over which select proteins remained greater than 80%soluble as determined by Bradford and the A650 value are listed in TableE31C.

TABLE E31B Buffer composition for pH solubility screen. Sodium mL of 42mM Phosphate Citric Sodium mL of 42 mM Buffer Dibasic Acid PhosphateCitric Add # pH (mM) (mM) (10 mL total) (10 mL total) 1 7.1 38 4 9 1 26.5 34 8 8.1 1.9 3 6 32 10 7.6 2.4 4 5.6 30 12 7.1 2.9 5 5 28 14 6.7 3.36 4.6 26 16 6.2 3.8 7 4.3 24 18 5.7 4.3 8 3.9 22 20 5.2 4.8 9 3.7 20 224.8 5.2 10 2.8 10 32 2.4 7.6

TABLE E31C Solubility of proteins over a range of pHs. pH Range whereProtein is >80% detected as Soluble and A650 <1 OD Protein High LowOther SEQID-00009 9.1 3.7 SEQID-00076 7.1 4.6 SEQID-00085 7.1 7.1SEQID-00100 7.1 4.3 SEQID-00103 7.1 5.6 SEQID-00104 7.1 5 SEQID-001059.1 4.3 SEQID-00226 9.1 2.6 SEQID-00240 9.1 6.6 3.0-2.6 SEQID-00241 9.14.3 SEQID-00265 9.1 5.1 3 SEQID-00269 9.1 7.2 3.0-2.6 SEQID-00287 9.16.2 2.6 SEQID-00338 7.1 2.8 SEQID-00485 7.1 4.6 2.8 SEQID-00502 7.1 2.8SEQID-00510 7.1 6.5 2.8 SEQID-00511 7.1 5.6 SEQID-00587 7.1 2.8SEQID-00605 7.1 5.6 SEQID-00622 7.1 2.8 N/A: not applicable.

Thermostability.

The thermostability of proteins in a buffer cocktail of Citric Acid andDibasic Sodium Phosphate over a pH range of 2.8 to 7.1 (preparationdescribed above in Table E31B) was determined using the ProteoStat® kThermal Shift Stability Kit (Enzo Life Sciences) according to themanufacturer's standard protocol. Briefly, protein solutions (˜10 mg/ml)containing 1× ProteoStat® TS Detection Reagent were heated from 25° C.to 95° C. at a rate of 0.5° C. per 30 sec using a real-time PCR (rtPCR)thermocycler (BioRad) equipped with a plate reader (SynergyMx, Biotek)while monitoring the fluorescence with a Texas Red filter. Thetemperature of aggregation (Tagg) was identified as the temperature atwhich the steepest slope was observed in the trace of fluorescenceintensity as a function of temperature. The temperature of aggregationat pH 7.1 for a subset of proteins is listed in Table E31D. Thetemperature of aggregation over a range of pHs for a subset of proteinsis listed in Table E31E.

TABLE E31D Temperature of aggregation (Tagg) at pH 7.1 Protein Tagg (pH7.1) SEQID-00008 >95 SEQID-00009 56 SEQID-00087 >95 SEQID-00099 64SEQID-00102 >95 SEQID-00220 >95 SEQID-00226 >95 SEQID-00237 45SEQID-00240 >95 SEQID-00241 >95 SEQID-00265 >95 SEQID-00269 >95SEQID-00302 46 SEQID-00305 48 SEQID-00510 57.5 SEQID-00606 95SEQID-00610 54.5

TABLE E31E Temperature of aggregation (Tagg) as a function of pH.T_(agg) pH pH pH pH pH pH pH pH pH pH Protein 7.1 6.5 6.0 5.6 5.0 4.64.3 3.9 3.7 2.8 SEQID-00076 >95 95 95  73.5 75 34.5 NS NS NS NSSEQID-00098 >95 NS NS NS NS NS NS NS NS NS SEQID-00100 >95 95 95 95 9584  83  95 95 95 SEQID-00103 >95 95 67.5 62 61 59.5 37.5  41.5  45.5 NSSEQID-00104 >95 95 95 80 66 59.5 60   74.5 NS NS SEQID-00105 >95 95 95 70.5 75.5 61.5 36.5 NS NS NS SEQID-00338 51.5 51 51.5 51 50.5 84.5 40.538 37 95 SEQID-00485 36 36.5 36  34.5 31.5 NS NS NS NS NS SEQID-00502 9578.5 76.5 77 77 95  95  NT 95 95 SEQID-00511 42 45.5 39.5 NS NS NS NS NSNS NS SEQID-00559 64.5 64 62 59 57 57.5 NS NS NS NS SEQID-00587 95 95 95 69.5 67 63  58.5 54  50.5 50 SEQID-00601 48.5 45.5 NS NS NS NS 95  NT95 95 SEQID-00605 39 38.5 44.5 37 33.5 40.5 NS NS NS NS SEQID-00622 9547 46  45.5 42.5 43.5 43.5 42 42  58.5 NS = condition where protein wasnot soluble for thermal stability assay.

Thermal Unfolding.

Thermal unfolding of proteins was monitored by circular dichroism on anApplied Photophysics CS/2 Chirascan spectrophotometer. Far-UVmeasurements (200-260 nm) of protein solutions (0.5 to 1.0 mg/mL) inbuffer (20 mM potassium phosphate, pH 7.5) were recorded every 5° C.from 20 to 90° C. using a 0.1 cm optical path length cell. Aftercollection of the spectrum at 90° C. the protein sample was immediatelycooled to 20° C. and a final spectrum was recorded. The meltingtemperature (Tmelt) was calculated as the temperature with the strongestslope, and the final spectrum was compared to the initial 20° C.spectrum to determine if protein unfolding was reversible or if apermanent change in structure had occurred. FIG. 48 displays arepresentative CD spectra of SEQID-00105, demonstrating the nutritivepolypeptide does not completely unfold at even 90 C and returns to it'soriginal fold when cooled to 20 C.

Example 32 Nutritive Polypeptide Glycosylation

The glycans present on proteins often affect properties such assolubility, activity, and stability. Changing the pattern onglycosylation of nutritive peptides can also affect theirbioavailability, nutritional quality, and product formulationattributes. Furthermore, specific sugar patterns on nutritive foodpeptides augment metabolic response to the ingestion of isolatednutritive food peptides based both the kinetics of amino acid absorptionand the incorporation of exogenous glycans during human proteinproduction.

Host Selection for Glycosylation State.

As described herein nutritive polypeptides were produced in a variety ofhosts. Choice of host has an impact on the glycosylation state of thenutritive polypeptide which has biophysical, digestion, and immunogenicimplications. For example, hosts for expression include. E. coli, B.subtilis. B. licheniformis, Aspergillus niger. Aspergillus nidulans,human embryonic kidney (HEK), and chinese hamster ovary cells (CHO). E.coli, B. subtilis and Bacillus licheniformis are used as an expressionhost due to their ability to produce polypeptides with unglycated (orminimally glycated) backbones compared to eukaryotic hosts such asaspergillus, s, cerevisiae, and pichia. Aspergillus niger is selected asa protein secretion host due to its unique glycosylation machinery thatdrives the addition of mannose-rich glycans to the polypeptide backbone.Aspergillus nidulans is selected as a protein secretion host, due to thepreviously demonstrated ability (Kainz et. al. N-Glycan modification inaspergillus species. Appl. Environ. Microbiol., 2008) to engineer thehost glycosylation machinery towards reduced glycan structure complexityin to place of extensive oligomannose polysaccharides. Chinese hamsterovarian (CHO) cells are selected as an expression host for their abilityto glycosylate proteins in patterns similar to human cells. Differencesinclude the Gal α1-3 Gal epitope and the N-glycolylneuraminic acid(Neu5gc) have both been found on glycoproteins produced by CHO cells butare not found in normal human glycans (Gahll, Un, et al Journal ofBiological Chemistry 263.33 (1988): 17755-17762). Also, certain proteinsproduced in CHO cells have more acidic isoforms suggesting highercontent of sialic acid. Human Embryonic Kidney 293 (HEK293) cells areselected as an expression host for their ability to have humanglycosylation of proteins.

Gel Electrophoresis and Protein Transfer.

To analyze glycosylation, western blot analysis was performed withantibodies or lectins that recognize specific glycan antigens toevaluate and compare the glycosylation profile of proteins produced ineukaryotes and prokaryotes. First, protein separation was performed bygel electrophoresis using Novex® NuPAGE® Bis-Tris Pre-cast gels (LifeTechnologies) according to the manufacturer's protocol. Proteins weretransferred from the gel to a nitrocellulose membrane using the iBlot®Dry Blotting System (Life Technologies) and iBlot® Western Detection Kit(Life Technologies) according to the manufacturer's protocol. Proteinbrands were visualized by staining polyacrylamide gels with Coomassie®G-250 stain SimplyBlue™ SafeStain (Life Technologies) according to themanufacturer's protocol and imaged using the Molecular Imager® Gel Doc™XR+ System (Bio-Rad).

Glycosylation Profile of SEQID-00363 Expressed in E. coli and A. niger.

The mannose content of proteins was examined using a glycoproteindetection kit (DIG Glycan Differentiation Kit. Roche) according to themanufacturer's standard protocol. To begin, whole cell extract (5 μg)and soluble cell lysate (5 μg) from E. coli transformed with anexpression vector encoding the gene for SEQID-00363 (as describedherein), SEQID-00363 expressed in A. niger (5 g), and the DIG GlycanDifferentiation Kit positive control carboxypeptidase Y (5 μg) wereloaded onto a Novex® NuPAGE® 10% Bis-Tris gel (Life Technologies).Protein separation and transfer were performed as described herein.Briefly, nitrocellulose membranes were incubated with digoxifenin(DIG)-labeled Galanthus nivalis agglutinin (GNA), a lectin that bindsterminal mannose. Membranes were then incubated withanti-Digoxidenin-alkaline phosphatase (AP), followed by incubation withan AP substrate solution (NBT/BCIP). The intensity of AP staining wasqualitatively visualized by the naked eye and membranes werephotographed. FIG. 49 displays a representative Coomassie-stained gel(panel A) and a GNA probed western blot membrane (panel B) ofSEQID-00363 isolated from A. niger and SEQID-00363 expressedrecombinantly in E. coli. In lane 2, a prominent band around 120 kD isrepresentative of glycosylated SEQID-00363. In lane 3, a band around 80kD is representative of non-glycosylated SEQID-00363. These resultsdemonstrate that SEQID-00363 expressed in A. niger (FIG. 49B, Lane 2) isa terminally mannosylated protein (FIG. 49B. Lane 3), while SEQID-00363expressed in E. coli contains no terminal mannose residues on itsglycans.

Protein Extraction from Food for Glycan Analysis.

Flaxseed (Organic Brown Flaxseed, Farmers Direct Coop), chickpea(Garbanzo Beans, 365 Everyday Value Organic), corn (frozen, Super SweetBicolor Corn, 365 Everyday Value Organic), potato (conventional yellowpotato), mushroom (organic white mushroom), broccoli (frozen, BroccoliFlortes, 365 Everyday Value), tomato (conventional Roma tomato),blueberry (Organic Blueberries, Little Buck Organics), grape (OrganicRed Seedless Grapes, Anthony's Organic), beef (85% Lean Ground Beef),chicken (Ground Chicken Thighs, Boneless, Skinless, Airchilled), lamb(Ground New Zealand Lamb), turkey (Ground Turkey Thighs), cod (Wild CodFillet), and pork (Ground Pork) were purchased from Whole Foods. Venisonwas provided. Aliquots of each food source (50-2,500 mg) were frozen at−80. Proteins were extracted from the food source by grinding the samplewith a mortar and pestle before adding 1.0 mL of extraction buffer (8.3M urea, 2 M thiourea, 2% w/v CHAPS, 1% w/v DTT) and additional grindingwith the pestle. The samples were transferred to microcentrifuge tubesand agitated for 30 min at room temperature, followed by addition of 500AL of 100-μm zirconium beads (Ops Diagnostics) and further agitation foran additional 30 min. Samples were then lysed on a TissueLyser II(Qiagen) at 30 Hz for 3 min. centrifuged for 10 min at 21,130×g, andsupernatants were collected. Yeast (Nutritional Yeast, Whole Foods), soyprotein isolate (Soy Protein Powder. Whole Foods), and rice proteinisolate (Organic Rice Protein, Growing Naturals) were prepared bysolubilization in extraction buffer. The total protein concentration ofsamples was determined by Coomassie Plus Protein Assays (Pierce)according to the manufacturer's standard protocol.

N-Glycolylneuramink Acid (Neu5Gc) Detection by Western Blot Analysis.

N-glycolylneuraminic acid (Neu5Gc) is a sialic acid found on mostmammalian glycans, but is not present on human protein glycoproteins.Human biochemical pathways don't recognize the Neu5Gc sialic acid asforeign, leading to trace amounts found in human glycoproteins followinguptake into golgi and incorporation onto newly synthesized proteins.Despite integrating biochemically, however, the immune system recognizesas foreign the adjusted surface conformation containing anexternally-derived sialic acid, increasing the risk of many diseases.Anti-Neu5Gc antibodies, which have been detected in human plasma, causechronic inflammation in response to the ingestion of Neu5Gc containingprotein sources (Varki et. al. “Uniquely human evolution of sialic acidgenetics and biology”, PNAS 2011). The main sources of Neu5Gc includelamb, beef, pork, and even dairy products, with trace amounts also foundin fish (Tangvoranuntakul et al., 2003, PNAS, 100(21): 12045-12050).

Western blot analysis was performed with an anti-Neu5Gc antibody tocharacterize the Neu5Gc content of proteins extracted from food as wellas proteins expressed recombinantly by bacterial hosts. Proteins wereextracted from meat sources as described herein. Also, proteins wererecombinantly expressed in E. coli and/or B. subtilis by transformationwith individual expression vectors, as described herein, or bytransformation with a library of expression vectors, as described inherein. Proteins originating from individual expression vectors, and insome cases protein originating from a library of expression vectors,were purified by IMAC purification, as described herein. A mixture(Protein Mixture 1) of purified proteins recombinantly expressed in E.coli was prepared to contain each protein at a final concentration ofapproximately 1 mg/mL. The proteins included in this mixture, as well asthe species in which they are naturally produced, SEQID-00076 Cow,SEQID-00240 Cow, SEQID-00298 Cow, SEQID-00359 Sheep, and SEQID-00510Turkey.

A sample of each meat extract (beef, pork, deer, lamb, turkey, chicken,and cod), Protein Mixture 1., the 168 nutritive polypeptide libraryexpressed in E. coli (IMAC-purified lysate) and B. subtilis(IMAC-purified lysate and unpurified supernatant and lysate), and thecDNA Library expressed in E. coli (Rosetta, GamiB, and Gami2 solublelysate and Rosetta whole cell) and B. subtilis (PH951 Grac lysate) wereloaded onto a Novex® NuPAGE® 10% Bis-Tris gel (Life Technologies).Protein separation and transfer were performed as described herein.Neu5Gc was detected using the SNAP I.d.®, Protein Detection System(Millipore) according to the standard manufacturer's protocol withchicken anti-Neu5Gc (IgY) primary antibody (BioLegend) and goatanti-chicken IgY-horseradish peroxidase (HRP) secondary antibody, bothdiluted 3:5,000 in Blok™-PO Blocking Buffer. Blots were treated withLuminata Classico Western HRP Substrate (Millipore) according to themanufacturer's protocol and imaged using chemiluminescent detection onthe Molecular Imager®, Gel Doc™ XR+ System (Bio-Rad). FIG. 50 displaysrepresentative Coomassie-stained gels (panel A) and anti-Neu5Gc probedwestern blot membranes (panel B). These results demonstrate that whileNeu5Gc is present in proteins extracted from cow, pig, sheep, turkey,and chicken meat, it is not present in proteins from these animals thathave been recombinantly expressed in E. coli or B. subtilis.

Xylose and Fucose Detection by Western Blot Analysis.

Xylose and fucose are sugars that are often present on plantglycoproteins and can be immunogenic to humans (Bardor et al., 2003,Glycobiology, 13(6): 427-434). The xylose and fucose content of proteinsextracted from food sources and proteins recombinantly expressed bybacterial hosts was examined by western blot analysis using anti-Xyloseand anti-Fucose antibodies. As described herein, protein samples wereprepared either by extraction from food sources or by reconstitution ofpurchased protein isolates. Proteins were recombinantly expressed in E.coli and purified by IMAC purification, as described in herein. Amixture (Protein Mixture 2) of purified proteins recombinantly expressedin E. coli was prepared to contain each protein at a final concentrationof approximately 1 mg/mL. The proteins included in this mixture, as wellas the species in which they are naturally produced, are SEQID-00103Rice. SEQID-00104 Corn, SEQID-00352 Corn, SEQID-00485 Chickpea,SEQID-00559 Rice, SEQID-00598 Flaxseed, and SEQID-00605 Mushroom.

A sample of each plant and fungi extract (yeast, flaxseed, chickpea,corn, potato, mushroom, soy, rice, broccoli, tomato, blueberry, andgrape), Protein Mixture 2, horseradish peroxidase (positive control),and fetuin (negative control) were loaded onto a Novex® NuPAGE® 10%Bis-Tris gel (Life Technologies). Protein separation and transfer wereperformed as described herein. Western blot analysis was performed usingthe SNAP I.d.® Protein Detection System (Millipore) according to thestandard manufacturer's protocol. Xylose was detected by blotting withrabbit anti-xylose primary antibody (Agrisera) and donkey anti-rabbitIgG-HRP secondary antibody (abeam) diluted 3:5,000 and 3:2, 500 inBlok™-PO Blocking Buffer, respectively. Fucose was detected by blottingwith rabbit anti-fucose primary antibody (Agrisera) and donkeyanti-rabbit IgG-HRP secondary antibody (abcam) diluted 3:10,000 and3:3,000 in Blok™-PO Blocking Buffer, respectively. Blots were treatedwith Luminata Classico Western HRP Substrate (Millipore) according tothe manufacturer's protocol and imaged using chemiluminescent detectionon the Molecular Imager® Gel Doc™ XR+ System (Bio-Rad). FIG. 51demonstrates a representative Coomassie-stained gel, anti-xylose probedwestern blot membrane, and anti-fucose probed western blot membrane.These results demonstrate that while xylose and fucose are both presentin plant proteins extracted from flaxseed, chickpea, corn, potato, soy,rice, broccoli, tomato, blueberry, and grape, they are not present inproteins from plant and fungi sources that have been recombinantlyexpressed in E. coli.

Selection of Proteins with High Asparagine, Serine, and/or ThreonineMass Compositions to Decrease Nutritive Polypeptide Glycosylation.

The glycosylation state of a nutritive polypeptide can be decreased byselecting sequences low in glycosylation sites. These sites includeAsparagine, for N-linked glycosylation, and serine and threonine, forO-linked glycosylation. These isolated polypeptides contain a higheramino acid percentage by mass due to the reduced level of boundpolysaccharide composition along the polypeptide, allowing a higherdigestible amino acid dose per gram of nutritive polypeptide, and havereduced immune activity upon consumption. The N-linked glycosylation ofavailable glycan acceptor sites along a nutritive polypeptide backboneoccurs predominantly at Asparagine amino acid residues. Expression ofheterologous polypeptides selected for their low levels of Asparagineallows for polypeptides to be isolated with decreased glycan structures.The O-linked glycosylation of available glycan acceptor sites along anutritive polypeptide backbone occurs predominantly at Serine andThreonine amino acid residues. Expression of heterologous polypeptidesselected for their low levels of either Serine or Threonine allows forpolypeptides to be isolated with decreased glycan structures

Selection of proteins with high Asparagine, Serine, and/or Threoninemass compositions to increase nutritive polypeptide glycosylation. Theglycosylation state of a nutritive polypeptide can be increased byselecting sequences rich in glycosylation sites. These sites includeAsparagine, for N-linked glycosylation, and serine and threonine, forO-linked glycosylation. Increase in glycosylation can enable increasedsolubility and thermostability of the nutritive polypeptide. TheN-linked glycosylation of available glycan acceptor sites along anutritive polypeptide backbone occurs predominantly at Asparagine aminoacid residues. Expression of heterologous polypeptides selected fortheir high levels of Asparagine allows for polypeptides to be isolatedwith increased glycan structures. The O-linked glycosylation ofavailable glycan acceptor sites along a nutritive polypeptide backboneoccurs predominantly at Serine and Threonine amino acid residues.Expression of heterologous polypeptides selected for their high levelsof either Serine or Threonine allows for polypeptides to be isolatedwith increased glycan structures

Removal of Glycans from Isolated Nutritive Polypeptides.

The glycosylation state of nutritive polypeptides can have an effect onstructure and physical properties. As described herein, nutritivepolypeptides expressed in recombinant hosts can have a differentglycosylation than occurs naturally. If a nutritive polypeptide isproduced with glycosylation, the glycans can be released to alterstructural and physical properties using chemical or enzymatic methods.Common chemical methods of glycan release are hydrazinolysis andalkali/reducing conditions (β-elimination) (Takasaki. Seiichi, et al.Methods in enzymology 83 (1981): 263-268.). Glycans can be released fromproteins using an Endoglycosidases such as PNGaseF, Endo-H, Endo F2,PNGaseA, or O-Glycanase or using an Exoglycosidases such as Sialidase,Alpha Galactosidase, Beta Galactosidase, Hexosaminidase,Galactosaminidase, Alpha Mannosidase, Beta Mannosidase, AlphaFucosidase, exact enzymes are selected based on oligosaccharidecomposition and linkage (Merry. Tony, et al. Capillary Electrophoresisof Carbohydrates. Humana Press, 2003, 27-40.).

PNGCase F is a very effective enzymatic method for removing almost allN-linked oligosaccharides from glycoproteins. PNGase F digestiondeaminates the aspargine residue to aspartic acid, and leaves theoligosaccharide intact. To deglycosylate a protein using anEndoglycosidase, 500 ug of glycoprotein is resuspended in 50 ul of 50 mMsodium phosphate pH 7.5. PNGase F is added at 0.1 U/ml and the solutionis incubated at 37 C for 24 hours. The reaction is monitored forcompletion by SDS-PAGE.

Screening for IgE-Mediated Allergic Response Due to Glycan.

A change in glycan modifications to a nutritive polypeptide affects theIgE binding interactions. About 20% or more of allergic patientsgenerate specific anti-glycan IgE, which is often accompanied by IgG(Altmann, F. The role of protein glycosylation in allergy. Int ArchAllergy Immunol. 2007). For polypeptides which induce an IgE-mediatedimmune response, as is the case with allergens, a glycan modification asdescribed herein may reduce the isolated polypeptide's allergenicitycompared to in its native composition. In this example, polypeptides arescreened for IgE binding in an in-vitro serum assay as well as forreactivity by skin prick test (as described in Mari. A et. al. IgE toCross-Reactive Carbohydrate Determinants: Analysis of the Distributionand Appraisal of the in vivo and in vitro Reactivity, 2002).

Allergenic response due to the glycan (termed cross-reactivecarbohydrate determinants), can be determined by comparing results of askin prick test with an IgE serum binding assay. Unselected consecutivesubjects presenting respiratory symptoms that suggest an allergicdisease, and referred to an allergy unit, are enrolled. Demographicaland clinical data are recorded for each patient. Patients with aclinical history of anaphylaxis are excluded from the study. Thosepatients who haven't previously received a specific immunotherapy (SIT)course are not excluded. All the treated patients receive alum-adsorbedextract of the nutritive polypeptide in both the isolated form and inthe native composition. For statistical purposes, only pollen treatedpatients are evaluated. Patients undergo skin prick testing (SPT), witha standardized procedure and recording (Mari. A, et. al Specific IgE tocross-reactive carbohydrate determinants strongly affect the in vitrodiagnosis of allergic diseases. J Allergy Clin Immunol 1999), using theallergenic extracts described above. Following the SPT, sera areobtained from patients who consent to blood sampling for an in vitrodiagnostic procedure. Sera are stored at −20° C. until required.Informed consent for skin testing and blood sampling is obtained bypatients or caregivers during the allergy consultation.

Total IgE is determined in all the sera (Radim, Pomezia, Italy).Allergen-specific IgE is detected by the CAP system following themanufacturer's instructions (Pharmacia, Uppsala, Sweden). Values 60.4kUA/l is considered positive. As there is not a single test to detectCCD-IgE, discrepancy of the results between a positive in vitro test tothe nutritive polypeptide bearing carbohydrate moieties recognized byIgE and a negative SPT to the same glycoprotein is assumed to beindicative of the presence of CCD-IgE. IgE detection is performed on thelargest random samples of sera recorded negative in the SPT to the sameallergenic extract. Modification in the glycan structure that mediatesbinding to IgE is observed by a shift in the distribution in patientsfor which a CCD-IgE is detected upon isolation of the nutritivepolypeptide and confirmation of altered glycan structure.

Example 33 In Animal Demonstration of Nutritive Polypeptide Amino AcidPharmacokinetics

Pharmacokinetic (PK) studies may be performed to evaluate the plasmaconcentration of amino acids following oral administration of anutritive polypeptide formulation. Such analyses provide information onthe rate and extent of digestion of the protein in the gastrointestinalintact and the bioavailability of the free amino acids and/or peptidesreleased during digestion. Growing rats, which have a similar smallintestinal transit rat to adult humans (3-4 h), are accepted as asuitable model for pharmacokinetic studies with oral administration(DeSesso and Jacobson (2001) Anatomical and physiological parametersaffecting gastrointestinal absorption in humans and rats, Food andChemical Toxicology 39: 209-228).

Rat Pharmacokinetic Studies.

Male Sprague Dawley rats with indwelling jugular vein cannula (JVC) werepurchased from Harlan Laboratories and acclimated to the Test Facility(Agilux Laboratories) for at least two days prior to study initiation.Prior to dose administration animals were fasted overnight (11-13 h) andremained fasted until completion of the study. Test articles were orallyadministered via a bulb-tipped 18 gauge stainless steel gavage needleattached to a syringe. The weight of all dose syringes were recordedprior to and following dosing to more accurately determine the amount ofsolution dosed. Serial blood samples (˜300 μL) were collected from theJVC at time 0 (pre-dose) and 0.25, 0.5, 1, 2, and 4 h post-dose. Bloodsamples were collected into tubes containing the anti-coagulant K2EDTA,a general protease inhibitor cocktail (Sigma P8340, diluted 1:100 inwhole blood), and a DPP IV inhibitor (Millipore DPP4, diluted 1:100 inwhole blood). Immediately following blood collection tubes were vortexedand stored on wet ice until processing to plasma by centrifugation(3,500 rpm at 5° C.) within 1 h of collection. Plasma samples were thentransferred into new tubes and stored at −80° C. In some cases,following the terminal blood collection animals were euthanized and theterminal ileum and its contents were collected and analyzed as describedherein.

The concentration of Glu, Ser, His, Gly, Thr, Arg, Ala, Tyr, Val, Met,Phe, Ile, Leu, and Lys in the plasma samples was determined by HPLCamino acid analysis, as described herein. Prior to HPLC amino acidanalysis, insoluble particles were removed from plasma samples bycentrifugation (1100×g at 4° C.) for 10 min. A 25 μL sample of thesoluble fraction was then transferred to a 96-well plate, for somesamples an internal standard (Norvaline, Agilent) was added to eachplasma sample at final concentration of 0.5 mM. Amino acids not measuredin the current HPLC amino acid analysis, including Gln, Asn, Trp,Hydroxyproline (Hyp), and Sarcosine (Sar), are analyzed by using astandard mixture that includes the individual standard stocks providedin the supplemental amino acid kit (Agilent) and comparing thechromatographic profiles of the samples against that of the combinedstandards. Because solutions containing the supplemental standards areunstable at room temperature the supplemental amino acid standards areprepared immediately prior to use and used for no longer than 24 h.

FIG. 52 displays the change in average area under the curve (AUC) (±SD)of plasma amino acid concentrations (μM.h) measured in blood samplescollected from rats over 4 h following oral administration of theindicated nutritive polypeptides at the doses listed in Table E33A. FIG.53 shows SEQID-00105 as an example of oral administration of nutritivepolypeptides altering the concentration of amino acids in rat plasma.The profile of amino acids detected in the rat plasma after oraladministration was dependent on the amino acid sequence of the nutritivepolypeptide. For example, oral administration of the polypeptidesSEQID-00240, SEQID-00338, and SEQID-00352 increased the change in AUC0-4h for plasma Lys, whereas administration of the polypeptidesSEQID-00363, SEQID-00424, and SEQID-00426 did not alter the change inAUC0-4 h for plasma Lys (FIG. 52). Additionally, the nutritivepolypeptide SEQID-00240 serves as an example of a polypeptide that iscapable of delivering essential amino acids (EAAs) while causing no fluxin plasma Phe concentration. FIG. 54 demonstrates representative plasmaamino acid concentration time curves for oral administration ofSEQID-00105 (2.85 g/kg) to rats. FIG. 54 demonstrates a dose-responseeffect on plasma Leu concentrations following oral administration ofSEQID-00105 at the doses indicated in Table E33A. Taken together, theseresults demonstrate that oral administration of nutritive polypeptidescan be used to deliver specific amino acid profiles to the systemiccirculation in rats.

TABLE E33A List of the nutritive polypeptides and doses used in ratpharmacokinetic studies. FIG. 52 and 53 Symbol SEQID Dose (g/kg) 1Vehicle NA 2 105 2.85 3 240 1.54 4 338 2.85 5 352 2.85 6 363 2.85 7 4232.85 8 424 2.85 9 425 2.85 10 426 2.85 11 429 2.85 12 559 2.85 13 5872.85 14 105 1.78 15 105 1.78 16 105 1.11 NA: not applicable.

Example 34 Modulation of Nutritive Polypeptide Digestibility

Multiple methods of protein modification were used to alter thestructure of a model nutritive polypeptide, SEQID-00363. These methodswere performed to assess the relevance of specific structural featuresin regards to protein digestibility and bioavailability. Thesemodifications include reduction of glycans, hydrolysis of the protein,reductionialkylation of disulfide bonds, and thermal denaturing ofprotein structure. Resulting materials from these modifications wereevaluated for improved digestion using in vitro digestion assays and, insome cases, in vivo assays. These methods or other means of producingsimilar structural changes end can be applied to other nutritivepolypeptides.

Enzymatic Deglycosylation.

It is predicted that SEQID-00363 contains high-mannose O-linkedglycosylation (Goto et al., 2007 Biosci. Biotechnol. Biochem.). Toassess the effect of glycosylation on the digestion of SEQID-00363 themannose glycans were significantly reduced enzymatically. A non-specificalpha mannosidase (M7257, Lot SLBC4303V, Sigma Aldrich. St. Louis, Mo.)was used to cleave all 1-3, 1-4 and 1-6 glycosidic linkages within theO-glycans. This alpha mannosidase does not cleave any non-mannoseglycosidic linkages; it is predicted that this enzyme is ineffectiveagainst N-linked glycan release.

The deglycosylation reaction was adapted from Jafari-Aghdam et al., 2005Biochimica et Biophysica Acta. The protein stock of SEQID-00363 wasresuspended from lyophilized powder to an enzyme concentration of 100g/L into deglycosylation reaction buffer: 20 mM sodium acetate, 2 mMzinc chloride, 0.01% 2-mercaptoethanol, pH 4.3. Reagent stocks werediluted into the deglycosylation reaction to a final volume of 0.5 L.The reaction was performed at a SEQID-00363 concentration of 10 g/L andan alpha mannosidase concentration of 0.5 EU per mg of SEQID-00363. Thereaction was sterile filtered through a 0.2 um filter directly into 7×70mL 3.5 kD dialysis cassettes in 20 L of deglycosylation reaction buffer.The reaction was performed in dialysis in order to decrease proposedfeedback inhibition of the alpha mannosidase by released(mono/poly)saccharides. The reaction was then stored at 37° C. for sixdays. Throughout the course of the reaction, approximately 10% ofSEQID-00363 was lost due to insoluble aggregate formation. At theterminal (6 day) time point, the reaction was collected from dialysis,sterile filtered, concentrated, and diafiltered into 10% (phosphatebuffered saline, pH 7.4. Successfully reduction of mannose glycans wasmonitored by a decrease in size by SDS-PAGE and anti-GNA western blot asdescribed herein. In order to create a high protein concentrationformulation of deglycosylated SEQID-00363, the remaining pool wasconcentrated in an Amicon spin concentrator (EMD Millipore, Billerica,Mass.) until the final concentration approached 250 g/L. Thehigh-concentration formulation remained soluble at 4° C., and was heldat that temperature for long-term storage.

Protein Hydrolysis.

Another approach to increasing bioavailability relative to a preparationof native protein was hydrolysis into short peptides. Proteinhydrolysates of commodity proteins, such as whey (Perea et al., 1993Enzyme Microb. Technol.) and soy (Kong et al., 2008 BioresourceTechnology) are generated enzymatically through subtilisin-mediatedproteolysis.

Subtilisin is most active at pH 8.5 and 55° C. (Alder-Nissen, 1986). Forthe intent of this experiment, a lyophilized preparation of a modelprotein enzyme was resuspended to 275 g/L in 100 mM sodium carbonate inorder to bring the pH of the resulting protein solution to approximatelypH 8. Subtilisin (Alcalase 2.4 L, Sigma Aldrich, St. Louis, Mo.) wasadded to the protein solution at a concentration of 5.93×10-4 U per mgof model protein enzyme. The reaction was then diluted to 250 g/L modelprotein enzyme and transferred to 55° C. for 24 hours. Once completed,the hydrolyzed material was stored at 4° C.

Reaction progress was monitored by size exclusion chromatography (SEC)using a Superdex 75 (5×150 mm) column (GE Healthcare, Uppsala, Sweden)and also by SDS-PAGE analysis.

Protein Reduction and Alkylation.

Disulfide containing proteins can be reduced and alkylated in order tobreak disulfide bonds and stabilize free thiols. This modificationdisrupts all disulfide bridge structure and furthermore preventsdisulfide bridges from reforming both intramolecularly orextramolecularly. SEQID-00363 contains 10 cysteines, and four disulfidebonds as predicted by SCRATCH Protein Predictor (Cheng et al., 2005Nucleic Acids Res.).

SEQID-00363 was reduced and alkylated at a final concentration of 6 g/Lusing Bio-Rad ready Prep Reduction/Alkylation Kit (Bio-Rad, Hercules,Calif.). The reduction/alkylation reaction was performed as recommendedby the manufacturer's instructions. SEQID-00363 was reduced andalkylated in 50 mM phosphate, pH 8.0. Samples were analyzed bynon-reducing SDS-PAGE analysis.

Heat-Induced Protein Destabilization.

Denaturation of protein involves the disruption of ordered structure ofthe molecule; i.e., reduction of all quaternary, tertiary and secondarystructure to primary structure. Denaturation disrupts all non-covalentintramolecular interactions; i.e., hydrogen bonding, ionic interaction,Vander Waals interaction and hydrophobic interaction. Heat can be usedto disrupt these interactions, and reduce a native protein to itsprimary structure (with the exception of disulfide linkages).

SEQID-00363 was diluted to 30 g/L in 10% PBS, pH 7.4 and rapidly heatedto 95° C. Upon boiling, the protein was removed from heat treatment andimmediately transferred to in vitro digestion analysis as described inherein.

In Vitro Digestibility of Modified Forms of SEQID-00363.

The digestibility of native SEQID-00363 and modified forms (ie,deglycosylated, reduced and alkylated, and heat-denatured) ofSEQID-00363 was evaluated using the methods described herein. Briefly,native and modified forms of SEQID-00363 were treated with simulatedgastric fluid (SGF) and the presence of intact protein remaining atvarious time points was analyzed by gel electrophoresis as describedherein. Additionally, the amount of free amino acids present afterexposure to a Pancreatin-based simulated digestive system was analyzedby reverse phase HPLC amino acid analysis as described herein. Resultsfrom the SGF digest of native and modified forms of SEQID-00363demonstrate that modification of SEQID-00363 via deglycosylation,reduction and alkylation, and heat-denaturation enhances thedigestibility of the protein to varying degrees. Results from thePancreatin digest of native and modified forms of SEQID-00363demonstrate that modification of SEQID-00363 via deglycosylation andheat-denaturation, but not reduction and alkylation, enhanced therelease of free Leu during digestion. Table E34A lists half-life valuescalculated from the exponential decay curves and free Leu (SIM) at 120min time point.

TABLE E34A SGF Half-life (t½) in min and Free Leu (μM) at 120 min timepoint of Pancreatin digest of modified nutritive polypeptide Free Leu(μM) at 120 min time point of SGF Half-life (t½) in min Pancreatindigest SEQID-00363 36 574.2 Heat-denatured 20.4 763.5 SEQID-00363Reduced and alkylated 20.4 598.1 SEQID-00363 Deglycosylated 4.3 799.2SEQID-00363

Bioavailability of Modified Forms of SEQID-00363.

The bioavailability of native and modified forms (ie. deglycosylated andhydrolyzed) of SEQID-00363 was evaluated using the methods described inherein. Briefly, native and modified forms of SEQID-00363 were orallyadministered to intrajugular-cannulated rats and concentration of freeamino acids in plasma samples collected over a 4 h period was determinedby HPLC amino acid analysis. Amino acid analysis of plasma samplescollected in the rat pharmacokinetic study of native and modified formsof SEQID-00363 are displayed in FIG. 55. These results demonstrate thathydrolysis of SEQID-00363 increased the bioavailability of Leucine,Serine, Threonine, and in general essential amino acids (EAAs). Whiledeglycosylation of SEQID-00363 did not increase the bioavailability ofLeucine or EAAs, it did increase the bioavailability of Serine andThreonine.

Ileal Digestibility of Modified Forms of SEQID-00363.

Protein quality is a function of amino acid composition, digestibility,and bioavailability. Ileal digestibility assays may be used to measurethe difference between the contents (ie. amino acid, nitrogen, drymatter weight) of a protein and the contents of the digesta in theterminal ileum following ingestion of the protein. Results from ilealdigestibility assays can be used to calculate amino acid, nitrogen, anddry matter ileal digestibility coefficients and provide knowledge aboutthe protein's digestibility and amino acid bioavailability (Darragh andHodgkinson, 2000, Journal of Nutrition, 130(7): 1850S-1856S). Fecaldigestibility coefficients, determined over the entire digestive tract,tend to overestimate amino acid digestibility and bioavailability due tomicrobial metabolism in the large intestine. Since protein digestion andamino acid absorption occurs mainly in the upper small intestine and iseffTectively complete by the end of the ileum, ileal digestibilityassays are now accepted as the method of choice for determining proteinand amino acid digestibility in monogastric mammals. Growing rats, whichhave a similar small intestinal transit rate to adult humans (3-4 h),are accepted as a suitable model for ileal digestibility assays (Amidonet al., 1986, The Journal of Pharmacy and Pharmacology, 38(5): 363-368).

A rat pharmacokinetic study with oral administration of native andmodified forms of SEQID-00363 was performed as described herein. Theindigestible marker Cobalt-EDTA was formulated at 50 mg/L in the dosedprotein solutions to monitor differences in intestinal transit ratebetween treatment groups and individual rats. Following the final bloodcollection (at t=4 h) rats were euthanized and the terminal ileum (20 cmof small intestine prior to the cecum) and its contents (the digesta)were collected into a pre-weighed tube. The ileum was flushed withsaline and pooled with the digesta. The pH of the digesta was adjustedto ˜3.0 with HCl in order to inactivate all enzymes. The ileum sampleswere placed into separate pre-weighed 15 mL conical tubes. All sampleswere flash frozen in liquid nitrogen, and stored at −80° C. untilfurther analysis. Individual ileum and ileum content weights werecalculated and recorded for each sample.

A sample of the digesta, which exists as a heterogenous solutioncontaining insoluble particles, was used in the Coomassie Plus ProteinAssay, as described herein, to determine protein concentration. Theaverage total protein concentration in digesta samples harvested fromrats administered vehicle, native SEQID-00363, deglycosylatedSEQID-00363, and hydrolyzed SEQID-00363 was 0.1, 0.9, 0.9, and 0.3mg/mL, respectively. Based on the volumes of collected digesta the totalprotein mass in digesta samples harvested from rats administeredvehicle, native SEQID-00363, deglycosylated SEQID-00363, and hydrolyzedSEQID-00363 was 1.2, 6.9, 7.7, and 2.2 mg, respectively. These resultsdemonstrate that the concentration and total mass of protein is higherin the digesta of rats administered native and deglycosylatedSEQID-00363 than in rats administered either vehicle or hydrolyzedSEQID-00363. Together these results suggest that hydrolyzed SEQID-00363is more completely digested in the rat gastrointestinal system thaneither native or deglycosylated SEQID-00363.

To determine ileal digestibility coefficients an aliquot of the dosingsample and the ileal digesta sample are analyzed for total amino acidcontent by reverse phase HPLC amino acid analysis (Lookhart and Jones,1985, Cereal Chemistry, 62(2):97-102), total nitrogen content byKjeldhal analysis (Lynch and Barbano, 1999, JOURNAL OF AOACINTERNATIONAL, 82(6): 1389-1398), and Cobalt content by InductivelyCoupled Plasma Mass Spectrometry (ICP-MS) (Taylor, H. E., InductivelyCoupled Plasma-mass Spectrometry: Practices and Techniques. AcademicPress, 2001) to determine ileal amino acid and nitrogen digestibilitycoefficients.

Example 35 Treatment of Nutritive Polypeptides for Reduced Activity

Modification of enzymatically active nutritive polypeptides can alterboth the enzymatic activity, and the structural stability of theprotein. It can be advantageous for an orally administered nutritivepolypeptides to lack activity that is not required for delivery of aminoacid nutrients. Furthermore, deactivation is indicative ofdestabilization that can be more digestible and bioavailable than itsnative counterpart. Enzyme modification was achieved through eitherchemical or heat treatment(s). Enzymatic activity was measured throughan in vitro assay.

Activity Assay.

Inactivation of SEQID-00363 was tested by a glucoamylase activity assay.Glucoamylase acts to hydrolyze p-nitrophenyl-a-D-glucopyranoside top-nitrophenol (PNP) and glucose. The activity of the enzyme in units (U)per mL was determined by measuring the absorbance of release PNP at 400nm (method adapted from Glucoamylase Activity Assay (U.S. Pharmacopeia.Food Chemicals Codex, 8th edition; 2012:1314-1315.)) PNP standards at0.12, 0.06, 0.03, 0.015 and 0.0075 μmol/mL in 0.3 M sodium carbonatewere used to determine the millimolar extinction coefficient (e) usingthe follow equation: e=A400 nm/C where the average value consideredwhere A400 nm is the absorbance at 400 nm measured using aspectrophotometer with a 10 mm light path and C is the standardconcentration in μmol/mL. The samples were made at dilutions in 0.1 Msodium acetate pH 4.5 that fall in the absorbance range of thestandards. 100 μL of sample was incubated at 50° C. for 5 minutes priorto addition of 100 μL of PNPG solution (100 mg PNPG, dilute to 100 mL in0.1 M sodium acetate pH 4.5) that had been equilibrated at 50° C. for atleast 15 minutes. The sample was then incubated at 50° C. and 100 μL of0.3 M sodium carbonate added 10 minutes after PNPG addition to stop thereaction. The absorbance at 400 nm was then measured and the activity inU/mL calculated as follows: Activity=[(Asample−Ablank)×0.3 mL× DilutionFactor]/∈×10 min×0.10 μmol/min/unit×0.1 mL where Asample is the sampleabsorbance and Ablank is the blank absorbance at 400 nm, 0.3 mL is thevolume of the reaction, 10 min is the reaction time, 0.10 mol/min is theamount of PNP cleaved per unit of enzyme and 0.1 mL is the samplealiquot. 1:1:1: 0.1 M sodium acetate pH 4.5:0.3 M sodium carbonate: PNPGsolution is used as a blank. Activity is reported as specific activity(U/mL or U/mg) or as a relative activity (i.e. compared to a controlprotein).

Protein Modification for Deactivation.

Protein enzymes can be deactivated through chemical-induceddestabilization of the enzymatic active site of the molecule. Anexperiment was performed that screened a subset of reagents thatrepresented different chemical classes and mechanisms of actionincluding: Oxidation (Bleach. H2O2, ethylene oxide); Reduction (DTT,bME, TCEP); Chaotrope (CaCl2, Urea, Gnd HCl, NaSCN); High pH (Na2CO3,Tris Base. Na2HPO4); Low pH (Na3Citrate, Tris HCl, Acetic acid, Boricacid); Neutral pH (Na-Citrate. MOPS Acid, MES Acid, Na-Acetate);Detergents (Tween 80, Triton-X-100, CHAPS, SDS, MPD); Chelation (EDTA,citrate).

SEQID-00363 was formulated in water to 300 g/L and diluted 10× into anarray of chemical deactivation conditions (final concentration=30 g/L).SEQID-00363 was subsequently assayed for enzymatic activity after 10minutes of deactivation and 4 days of deactivation Table E35A.

TABLE E35A Chemical deactivation of SEQID-00363. Results of enzymeactivity assay at 4 day time point. All enzyme activities are normalizedto the negative control (water). Activity After Activity After 4 Days 4Days Condition (% of Water) Condition (% of Water) Water Control 100% 1M Gnd HCl 58% 1% Triton-X-100 93% 250 mM Tris Base 56% 200 mM CaCl2 92%100 mM Tris Base 54% 1% CHAPS 85% 2M Gnd HCl 46%  50 mM CaCl2 84% 500 mMTris Base 41% 400 mM CaCl2 79% 5M Urea 41% 100 mM CaCl2 78% 0.1% Bleach21% 5% BME 77% 50 mM Na2CO3 19% 250 mM EDTA 76% 10M Urea 15% 0.1% H2O276% 4M Gnd HCl 10% 0.01% Bleach 73% 0.615% Bleach  9% 50 mM DTT 73% 100mM Na2CO3  6% 0.3% H2O2 72% 200 mM Na2CO3  4% 1% Tween 80 66% 500 mMNa2CO3  0% 1% SDS 65% 6M Gnd HCl  0% 0.5M Gnd HCl 60%

Relative to a water deactivation negative control, SEQID-00363 displayedgreatest deactivation in strong chaotropes such as 6M Gnd.HCl and 4Murea; high pH formulations of sodium carbonate; and the strong oxidizer,sodium hypochlorite (household bleach). At t=4 days, these conditionsall displayed less than 20% of relative enzymatic activity after fourdays of treatment. Due to the health risks associated with consumptionof vigorous oxidizers and strong chaotropes, treatment of SEQID-00363with high pH was identified as the best condition for deactivation ofthe enzyme. Relative to the 10 minute time point, samples taken at thefour day time point suggest that chemical deactivation at roomtemperature is not a fast-acting process. The kinetics of deactivationare likely not very fast in many of the assayed conditions.

An experiment measured deactivation of SEQID-00363 by heat at multiplebuffer conditions was tested. SEQID-00363 was diluted to 3 g/L in 20 mMsodium phosphate pH 7, 20 mM sodium phosphate pH 9, 20 mM sodiumcarbonate pH 11 and water. 100 μL of sample was then treated at ambienttemperature, 60° C., 70° C., 80° C. and 90° C. for each buffer for 5minutes in a PCR thermocycler. The activity of each enzyme was tested bythe glucoamylase activity assay and each activity normalized to theactivity in water at ambient temperature (control). The results areshown below in Table E35B.

TABLE E35B Chemical deactivation of SEQID-00363. Results of enzymeactivity assay at 4 day time point. All enzyme activities are nomalizedto the negative control (water). Activity (% of Water, ConditionAmbient) Water, Ambient 100%  Water, 60° C. 84%  Water, 70° C. 14% Water, 80° C. 3% Water, 90° C. 3% 20 mM Sodium Phosphate pH 7, Ambient101%  20 mM Sodium Phosphate pH 7, 60° C. 53%  20 mM Sodium Phosphate pH7, 70° C. 2% 20 mM Sodium Phosphate pH 7, 80° C. 1% 20 mM SodiumPhosphate pH 7, 90° C. 1% 20 mM Sodium Phosphate pH 9, Ambient 99%  20mM Sodium Phosphate pH 9, 60° C. 27%  20 mM Sodium Phosphate pH 9, 70°C. 2% 20 mM Sodium Phosphate pH 9, 80° C. 1% 20 mM Sodium Phosphate pH9, 90° C. 1% 20 mM Sodium Carbonate pH 11, Ambient 93%  20 mM SodiumCarbonate pH 11, 60° C. 0% 20 mM Sodium Carbonate pH 11, 70° C. 0% 20 mMSodium Carbonate pH 11, 80° C. 0% 20 mM Sodium Carbonate pH 11, 90° C.1%

An additional multifactoral experiment was performed that assayed theeffect of temperature and pH for varying exposure time on the enzymaticactivity of SEQID-00363. SEQID-00363 was formulated to 100 g/L, and theeffect of either a high pH spike, or a diafiltration into high pHbuffers was tested against a gradient of temperatures across 25 C to 70°C. over a time course of 0 hours to 24 hours. Upon analysis, sampleswere neutralized to ˜pH 7 using a spike of 1 M sodium acetate buffer.

SEQID-00363 experimental overview and design was as follows. SEQID-00363was resuspended to 100 g/L and either spiked with 0.25M sodium carbonatepH 10, diafiltered into 50 mM sodium carbonate pH 10, or diafilteredinto 10% phosphate buffered saline pH 9.0. Samples were incubated ateither 40, 50, 60 or 70° C. across a time course that included samplingpoints at t=0, 1, 2, 4 and 24 h.

Inactivation of SEQID-00363 was assayed using an activity assay asdescribed herein. Samples were analyzed by specific activity (U/mg) andvisual solubility, as either a gel, viscous or fluid. This study foundSEQID-00363 is enzymatically deactivated by both temperature and pH.Some treatments caused irreversible aggregation, and gel formation ofthe nutritive polypeptide; these samples were not analyzed for enzymaticactivity. The results of this experiment suggest that SEQID-00363 can besolubly deactivated at pH 10 at 25° C. As the temperature of thereaction increases, the protein remains deactivated, but becomesinsoluble.

pH was therefore defined as a critical process variable in regard toSEQID-00363 deactivation. A subsequent study was performed to exploredSEQID-00363 deactivation as a function of pH at room temperature. Aprocess which can be performed at room temperature is less costly andeasier to scale up than a heated process. SEQID-00363 was formulated to100 g/L at pH 3.6 and using an ultrafiltration membrane, the buffer wasexchanged into a series of sodium carbonate buffers. The SEQID-00363solution pH increased from 3.6 to 11.0 during the course of bufferexchange. Samples of the protein were taken from the ultrafiltrationsystem systematically during the course of buffer exchange, resulting ina set of samples across the pH range. These samples were held at roomtemperature and each sample was split in half. Half of each sample wasneutralized into sodium acetate buffer after 2-5 hours. Neutralizedsamples were then assayed for enzyme activity as described and resultsare in the Table E35C.

TABLE E35C Effect of 2-5 hour incubation over pH range on activity.Relative activity pH (%) 3.6 100 4 91 5 83 6 82 7 89 8 86 9 56 9.7 54 1037 10.9 13

Deactivation by hydrolysis of SEQID-00363 was also tested byglucoamylase activity assay. The procedure of protein hydrolysis isdescribed herein. Hydrolysis was found to reduce activity to 7% relativeto control.

Other amylase nutritive polypeptide deactivation was also tested.Deactivation of SEQID-00424 was tested by the glucoamylase activityassay as described herein, but instead utilizing a pH 5.0 acetate buffer(recommended for Aspergillus oryzae derived enzymes). Samples weredeactivated by hydrolysis or by boiling, as described herein. Boilingreduced activity to 0% and hydrolysis reduced activity to 51% relativeto control.

Example 36 Disruption of Nutritive Polypeptide Enzymatic Activity

Construction of Mutant Proteins. Multiple mutations were tested todetermine the degree of enzymatic inactivation that could be achievedfor a model protein known to have enzymatic activity (SEQID-00338,UniProt ID: P07170). In this protein, the substrate binding sitesincludes positions 42, 134, 167, and 178. In addition, there is amagnesium ion binding site at position 91. Single amino acid mutationswere made at several substrate-binding positions. The mutants wereexpressed and tested for enzymatic activity.

The single amino acid mutant proteins were constructed by PCRamplification of two pieces. The first piece is amplified using aforward primer that binds to the 5′-end of the gene(ATCACCACCATCACCATCATAGCAGCAGCGAAACATTCGTATG) with an overhang that iscompatible with a His-tag and a reverse primer (Table E36A) containingthe most common codon for the target amino acid in Escherichia coli andthe 20-bp flanking region upstream and downstream of the mutation. Thesecond piece amplifies the 3′-end of the protein immediately followingthe mutation site using a forward primer specific to the position of themutation (Table E36A) and a reverse primer that binds to the 3′-end ofthe gene (TGTTAGCAGCCGGATCCTTAATCTTTGCCCAGCTTTATTCAGAATATC). StandardPCR reaction conditions were used for all pieces, which contains 0.5 uMforward primer, 0.5 uM reverse primer, 1× Phusion Polymerase Master Mix(New England Biolabs), and 1-100 ng template DNA in 50 ul final volume.The thermocycle conditions are initial denaturing at 98° C. for 30 sec.cycle 30 times with denaturing temperature at 98° C. for 10 sec.annealing temperature at 55-60° C. 15 sec, extension temperature at 72°C. for 15 sec/kb product. The template DNA are removed from the finalproducts by adding 1 ul Dpn I (New England Biolabs) and 5 ul 10×CutSmart buffer and incubating at 37° C. for 1 hour. Each PCR product iscleaned and concentrated following a Gel Recovery kit (Zymo Research)and eluted in 20 ul sterile water before proceeding to the next assemblystep.

TABLE E36A List of reverse primers used toamplify PCR piece 1 for the mutants. Mutation Reverse Primer 1  D91FGGAATGGTACGCGGAAAACCAAACAGAATAAAGCCATTT TTGCATGCC  D91IGGAATGGTACGCGGAAAACCAATCAGAATAAAGCCATTT TTGCATGCC R134MCCGCTTGCCGGATGAATCAGCATACCGGTAATACGTGCA ACCAG R134YCCGCTTGCCGGATGAATCAGATAACCGGTAATACGTGCA ACCAG  R42AGTACCTTTTGCAATCTGGCTTGCCAGCATATCACCGGTT GCCAG  R42CGTACCTTTTGCAATCTGGCTACACAGCATATCACCGGTT GCCAG  R42GGTACCTTTTGCAATCTGGCTACCCAGCATATCACCGGTT GCCAG  R42IGTACCTTTTGCAATCTGGCTAATCAGCATATCACCGGTT GCCAG  R42KGTACCTTTTGCAATCTGGCTTTTCAGCATATCACCGGTT GCCAG  R42LGTACCTTTTGCAATCTGGCTCAGCAGCATATCACCGGTT GCCAG  R42QGTACCTTTTGCAATCTGGCTCTGCAGCATATCACCGGTT GCCAG  R42TGTACCTTTTGCAATCTGGCTGGTCAGCATATCACCGGTT GCCAG  R42VGTACCTTTTGCAATCTGGCTAACCAGCATATCACCGGTT GCCAG Position Forward Primer 2 91 GGTTTTCCGCGTACCATTCC 134 CTGATTCATCCGGCAAGCG  42AGCCAGATTGCAAAAGGTACAC

Mutations are specified by original amino acid in its single letterabbreviation followed by the position and the final amino acid in itssingle letter abbreviation.

The PCR amplified pieces were inserted into the expression plasmid byGibson assembly and transformed into T7 Express (New England Biolabs)cells for expression. The expression plasmid pET15b containing a T7promoter, an 8×His-tag, and a stop codon was amplified by PCR usingprimers GGATCCGGGCTCTAACAAAGCC and ATGATGGTGATCGTGGTGATGATGATGAC so thatthere will be 20 bp overlap between each PCR piece, so that they will beproperly assembled by Gibson assembly. In Gibson assembly, 1 ul of eachPCR piece is combined into 10 ul final volume with 1× Gibson AssemblyMaster Mix (New England Biolabs) and incubated at 50° C. for 1 hour. Theassembly reaction mixture was diluted 3× by adding 20 ul water. 3 ul ofthe diluted mixture was transformed into 30 ul T7 Express (New EnglandBiolabs) cells. Single colonies were picked and plasmids extracted andsequence confirmed before moving on to expression studies.

Expression and Purification of Mutant Proteins.

Single colonies were used to inoculate a 2 mL deep well block with 1 mLof LB medium with 100 mg/L carbenicillin in each well. Cultures wereshaken at 37° C. and 900 rpm overnight in a deep well block shaker. Thedeep well block was used to inoculate another deep well block with 1 mLof BioSilta Enbase medium with 600 mU/L glucoamylase to an OD600 of 0.1.Cultures were shaken for 16 hours at 37 C and 900 rpm, at which point 1mM IPTG was added to induce the cultures, and additional Enbasesupplemental media and another 600 mU/L of glucoamylase was added tosupplement the cultures. Expression was carried out for another 6 hoursat 37° C. and 900 rpm. Cultures were harvested by spinning the deep wellblock at 3.000×g for 10 minutes at RT. After centrifugation, thesupernatant was carefully removed the cell pellets were frozen at −20°C. Frozen cell pellets were thawed and 0.3 g of 0.1 mm zirconium beadswere added to each sample followed by 0.5 ml of PBS. The cells werelysed in the cold room (4° C.) by head-beating for 5 min in a QiagenTissuelyserII (Qiagen. Hilden, Germany) equipped with a 96-well plateadapter. Cell lysates were centrifuged at 3000 rpm for 10 min and thesupernatant was removed, sampled, and analyzed for protein concentrationby chip electrophoresis. Samples were prepared by adding 2 μl of sampleto 7 μl sample buffer, heating at 95 C for 5 minutes, and then adding 35μl of water. Analysis was completed using HT Low MW Protein ExpressLabChip® Kit or HT Protein Express LabChip® Kit (following themanufacturer's protocol). A protein ladder ran every 12 samples formolecular weight determination (kDa) and quantification (ng/μl).

The mutant proteins were purified using the His Multitrap HP (GEHealthcare) system according to manufacturer's protocol. Theconcentrations of the proteins were measured by SDS-PAGE stained byCoomasie Blue and absorbance at 280 nm. The proteins were diluted in 40mM Tris buffer for kinase activity assay.

Determination of the Kinase Activity of SEQID-00338.

The ADP-Glo™ Max Assay was obtained from Promega (Catalog number V7001,Madison, Wis.). Adenosine Monophosphate was obtained from Sigma-Aldrich(Catalog number A1752, St. Louis, Mo.). 5× Kinase Buffer was prepared w/1.211 g Tris Base (Catalog number BP152-2, Fisher Bioreagents,Pittsburgh, Pa.), 692 μL 12% hydrochloric acid solution (Catalog numberBDH3026-500MLP, VWR, Radnor, Pa.), 10.0 mL 500 mM magnesium chloride(Catalog number BP214-500. Fisher Bioreagents. Pittsburgh, Pa.) and thevolume brought to 50 mL with MilliQ water and filtered through 0.22 μmPES filter (Catalog number SCGP00525, Millipore, Billerica, Mass.) intoa sterile 50 mL tube.

Twelve his-tag purified mutant proteins and the wild-type protein at 35μg/mL in Tris buffer were serially diluted to 7.0 and 1.4 μg/mL.Prepared kinase reaction mix at 0.5 mM AMP/0.5 mM ATP to test foractivity and at 0 mM AMP/0 mM ATP to assay background activity bydiluting 5× Kinase Buffer with appropriate volumes of 10 mM AMP and 10mM ATP in MilliQ water. Duplicate reactions were prepared by mixing 9 μLof the reaction mixture with 6 μL of diluted SEQID-00338, mixing bypipetting up and down and dispensing 5 μL into a 384-well whiteOptiPlate (PerkinElmer, Waltham, Mass.). An ADP standard curve wasprepared by serially diluting 4 mM ADP in MilliQ water and adding kinasebuffer to 1× for a standard at 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1,0.5, 1, 2, 3, and 4 mM ADP. The plate was covered with a foil plate sealand incubated at 30° C. for 30 min. Following the kinase reaction, 5 μLof ADP-Glo™ Reagent was added to each well. The plate was sealed with afoil plate seal and placed on a horizontal plate shaker at 450 rpm for 2minutes at mom temperature. The plate was removed from the plate shakerand incubated at room temperature for 40 minutes. The plate was thencentrifuged for 15 seconds at 1109×rcf and 10 μL of ADP-Go™ MaxDetection Reagent was added. The plate was sealed with a foil plate sealand shaken on a horizontal plate shaker at 450 rpm at room temperaturefor 2 minutes. The plate was then removed from the plate shaker andincubated at room temperature for 60 minutes. The plate was centrifugedfor 15 seconds at 1109×ref and the luminescence read on an EnspireAlphaplate reader (PerkinElmer, Waltham, Mass.).

The ADP standard curve was used to determine the concentration of ADP insample wells in the presence or absence of substrate. Concentrationswere determined by performing a non-linear 4 parameter logistic on theX=log(X) transformed ADP standard luminescence values. Background ADPwas found to be below the limit of detection in most samples. Where thebackground concentration of ADP in the absence of substrate wascalculable the average of those values were subtracted from thecalculated ADP concentration in the substrate incubated wells. Activityknock out was calculated by percentage activity relative to purifiedwild-type protein at the same concentration.

TABLE E36B The proportion activity was calculated as the percentageAMP + ATP→2ADP converted by SEQID-00338 at 7 μg/mL during a 30 minutereaction at 30° C. KINASE AVG SD N Wild-type 100.0%  11.2% 2 D91F 0.9%0.60% 2 D91I 0.4% 0.20% 2 R134M 0.3% 0.09% 2 R134Y 0.2% 0.08% 2 R42A0.9% 0.08% 2 R42C 1.8% 0.14% 2 R42G 1.2% 0.06% 2 R42I 1.5% 0.07% 2 R42K2.2% 0.14% 2 R42L 1.7% 0.08% 2 R42Q 1.2% 0.05% 2 R42T 1.9% 0.06% 2

Example 37 Engineering of Secreted Polypeptide for Reduced EnzymaticActivity

A mutant protein was constructed to reduce the enzymatic activity of anutritive polypeptide. The active sites of SEQID-00407 are predicted tobe residues D217 and E249, which are acidic residues lying in the centerof the catalytic domain. To produce a polypeptide free of enzymaticactivity and enriched in amino acids important to nutrition and health,we mutated those two sites to disrupt the catalytic activity ofSEQID-00407. D217 and E249 in SEQID-00407 may act as nucleophiles andproton donors or acceptors to form hydrogen bonds with their ligands.

To remove enzymatic activity from SEQID-00407, we engineered a proteinwith a single amino acid mutation at E249, changing it from glutamicacid to phenylalanine. The mutant was constructed by assembling two PCRfragments. The first contains the 5′-end of the enzyme up to 20 bpdownstream of the mutation site. The second contains the 3′-end of theenzyme starting immediately after the mutation site. In the first PCRfragment, specific PCR primers were designed to bind the targetedmutation site and incorporate the desired mutant amino acid codon. TheTTT codon was selected because it is the most highly used codon forphenylalanine in Bacillus subtilis. The two PCR fragments were assembledand inserted into the plasmid vector using Gibson Assembly method (NEBGibson Assembly Master Mix) at 50° C. for 1 hour. The constructs werebuilt in E. coli and confirmed by DNA sequencing before transforminginto Bacillus subtilis for secretion and enzymatic activity assays.

Secretion of nutritive polypeptides from Bacillus subtilis. Threeseparate colonies of B. subtilis expression strains were used toinoculate 1-ml of 2×L-Mal medium (20 g/l NaCl, 20 g/l tryptone, and 10g/l yeast extract, 75 g/l maltose) with Cm5, in deep well blocks(96-square wells). Culture blocks were covered with porous adhesiveplate seals and incubated overnight in a micro-expression chamber(Glas-Col. Terre Haute, Ind.) at 37° C. and 880 rpm. Overnight cultureswere used to inoculate fresh, 2×L-Mal, Cm5 cultures, in deep wellblocks, to a starting OD600=0.1. These expression cultures wereincubated at 37° C., 880 rpm until the OD600=1.0 (approx. 4 hrs) atwhich time they were induced by adding isopropylp-D-1-thiogalactopyranoside (IPTG) at a final concentration of 0.1 M andcontinuing incubation for 4 hrs. After 4 hrs, the cell densities of eachculture was measured (OD600) and cells were harvested by centrifugation(3000 rpm, 10 min, RT). After centrifugation, culture supernatant wascarefully removed and transferred to a new block and cell pellets werefrozen at −80° C. To determine the levels of secreted protein, thesupernatants were assayed to determine the levels of secreted protein ofinterest (POI) by chip electrophoresis. Briefly, samples were preparedby adding 2 μl of sample to 7 μl sample buffer, heating at 95 C for 5minutes, and then adding 35 μl of water. Analysis was completed using HTLow MW Protein Express LabChip® Kit or HT Protein Express LabChip® Kit(following the manufacturer's protocol). A protein ladder ran every 12samples for molecular weight determination (kDa) and quantification(ng/μl).

Amylase Activity Assay.

SEQID-00407 is an a-amylase in Bacillus subtilis that has the activityof breaking down polysaccharides, such as starch, into monosaccharidesor disaccharides. To demonstrate that the specific mutants have removedenzymatic activity, Bacillus subtilis secreting the enzyme were platedonto agar plates containing starch. If there is enzymatic activity, thesecreted enzyme will breakdown the starch and upon staining by iodine,there will be a halo surrounding the Bacillus subtilis colonies. 1%starch plates were made by combining 25 g Luria Broth-Miller, 10 gstarch, 15 g bacteriological agar, and 1 L water. 10 mM IPTG was addedto the starch plates after the agar has solidified. Single colonies ofBacillus subtilis strains expressing the mutant polypeptides wereinoculated in 5 ml LB at 37° C. for 4 hours and 50 μl of the liquidculture were spotted at the center for the starch plates. After 20 hoursof growth and induced secretion, 10% iodine was added to the starchplates to stain for starch. When the wild-type enzyme is secreted, itcreates a large halo around the cells. However, when the engineeredenzymes are secreted, the halo reduces in area, similar to the negativecontrol strain, which expresses the empty vector without the enzyme.Table E37A quantifies the area of the halos relative to the area of thecells. It is shown that the difference in area between the halo and thecells is larger for the wild-type than engineered mutants. From the datashown, we demonstrated the engineering of secreted nutritive polypeptidewith reduced enzymatic activity.

TABLE E37A Quantified area of cells, halos, and their differencesmeasured in in2. Protein Cell Area (in²) Halo Area (in²) Halo/Cell Noprotein control 0.413 0.6 1.45 Wild-type 1.27 2.246 1.77 E249F sample 10.331 0.496 1.50 E249F sample 2 1.335 1.936 1.45

Example 38 Engineering of Nutritive Polypeptide Amino Acid Content toModulate Polypeptide Activity and to Enrich Essential Amino Acid Content

To demonstrate the engineering of secreted polypeptides for enrichedamino acid content, we chose a microorganism known to secrete protein athigh levels Bacillus subtilis. SEQID-00407 was identified a majorsecreted protein in Bacillus subtilis. Using sequence conservation andcrystal structure data for SEQID-00407, we identified contiguous regionswithin each protein that were predicted to be tolerant to mutationswithout negatively affecting the structural stability of the proteinand/or the ability of the host organism to secrete the protein.

We analyzed the secondary structure of SEQID-00407 reported in thestructural protein databank entry 1UA7. We identified 19 loop regionswithin the sequence of the protein that are not part of an a-helix or aa-sheet. These loop regions are defined by the following amino acidresidues: 73-76, 130-133, 147-152, 157-161, 189-192, 222-227, 239-244,283-286, 291-298, 305-308, 318-323, 336-340, 356-360, 365-368, 387-392,417-421, 428-432, 437-442, and 464-466. Loop regions less than 4 aminoacids in length were not considered for mutation.

Conservation of sequence over evolutionary space was also considered foridentifying positions amenable for engineering while maintainingstructural stability and secretion competency. Positions that are lessconserved within a family of homologous sequences are inherentlyvariable and likely more amenable to mutation without affectingactivity, which is intrinsically tied to structure. To find positionsthat are less conserved, we downloaded the alignment of the pfam00128from the NCBI Conserved Domain Database, which contains 31 proteinsequences including the SEQID-00407 catalytic domain (Marchler-Bauer A.,Zheng C., Chitsaz F., Derbyshire M. K., Geer L. Y., Geer R. C., GonzalesN. R., Gwadz M., Hurwitz D. 1., Lanczycki C. J., Lu F., Lu S., MarchlerG. H., Song J. S., Thanki N., Yamashita R. A., Zhang D., and S. H.Bryant. Nucleic Acids Res. (2013) 41:D348-52). We also performed aPSI-BLAST search of the NCBI protein reference sequence database (PruittK. D., Tatusova T., and D. R. Maglott. Nucleic Acids Res. (2005)33:D501-504) using SEQID-00407 and obtained 500 sequences homologous toSEQID-00407. In both cases, a single iteration was performed using theBLOSUM62 position specific scoring matrix, a gap penalty of −11, a gapextension penalty of −1, and an alignment inclusion e-value cutoff of0.005 (Altschul S. F., Nucleic Acids Res. (1997) 25:3389-3402). Allprotein sequence alignments were used to generate position-specificscoring matrices (PSSM) specific to each query sequence as part of thePSI-BLAST search. From the PSSMs, we identified regions predicted to betolerant to mutation by counting the number of different amino acidsassociated with a positive PSSM score at each position within each loopas well as the sum and average of the PSSM scores for essential aminoacid substitutions at each position. Furthermore, from the multiplesequence alignments obtained from each PSI-BLAST search, we calculatedthe amino acid entropy at each position, as defined by

     ? = ? ?indicates text missing or illegible when filed

where Sj is the entropy at position j and pi is the probability ofobserving amino acid i at position j.

Using these measures of mutation tolerance, we identified four loopregions expected to be tolerant to mutations into essential amino acids.To enrich the identified regions in essential amino acids we used acombinatorial codon library where any selected position could be eithera F, I, L, V, or M (denoted Z) or a R, K, T, I, or M (denoted X). Ineach of the loop regions selected for mutation into an essential aminoacid, each variable position was assigned as a Z or X depending upon itsrelative tolerance of hydrophobic residues (based upon their respectivePSSM values). Positions that were tolerant of hydrophobic residues wereassigned as Z and genetically encoded using the codon NTN. Positionsmore tolerant of hydrophilic residues were assigned as an X andgenetically encoded using the codon ANR. We note that in one of theidentified variable regions of SEQID-00407 (147-153), a glycine residuewas inserted into the center of the loop in an attempt to enhance theconformational flexibility of this region. For SEQID-00407 the sequencesof the identified regions are summarized in Table E38A.

TABLE E38A Start residue # original degenerate 148 YAAI XXGXX 240 NTSAZXXZ 291 SHYASD XZYXXZ 389 QPEE XPZZ X = NTN, codes for F, L, I, M, V Z= ANR, codes for I, M, T, K, R

Library Design and Construction.

Based on identification of variable regions, we designed primers thatcan amplify each variable region as explained herein. For example ifthere are four variable regions, we need four pair of primers togenerate four variable fragments. In step 1 we used pES1205 as thetemplate which contains SEQID-00407 fused with N-terminal AmyQ signalpeptide and downstream of pirac promoter, pES1205 is a derivative of thevector, pHT43 (MoBiTec), containing a 1905-bp DNA fragment encoding theamyE gene from B. subtilis (minus the initial 93-bp encoding the AmyEsignal peptide) plus a C-terminal 1×FLAG tag. The amyE::1XFL:AG sequenceis cloned, in-frame with the SamyQ sequence encoded on pHT43. Forfragment 1, 2, 3, 4, the forward PRIMERID-45053, PRIMERID-45054,PRIMERID-45055, and PRIMERID-45056 contain 25 bases of constant sequencebefore the variable region followed by degenerate sequences to representthe variable region and 25 bases of constant sequence downstream of thevariable region. For fragment 1, 2, 3, the reverse primersPRIMERID-45061, PRIMERID-45062, and PRIMERID-45063 contain 25 bases ofreverse complementary sequence upstream of next variable regionrespectively. For fragment 4, the reverse primer PRIMERID-45064 contains25 bases of reverse complementary sequence at an arbitrary distance fromvariable region 4. Four separate PCR amplifications were run usingPhusion DNA polymerase (New England Biolabs, Beverly, Mass.) andreaction parameters recommended by the manufacturer. As separatereactions, four wild type fragments, WT-frag-1, WT-frag-2. WT-frag-3 andWT-frag-4 were generated using PES 1205 as template and primer pairsPRIMERID-45057 & PRIMERID-45061, PRIMERID-45058 & PRIMERID-45062,PRIMERID-45059 & PRIMERID-45063, and PRIMERID-45060 & PRIMERID-45064,respectively. All PCR fragments were gel purified. In step 2, twoseparate PCR reactions were set. The first PCR reaction contain fragment1 and 2 in equimolar ratio as template and PRIMERID-45057 andPRIMERID-45062 as primers. The second PCR reaction contain fragment 3and 4 in equimolar ratio and PRIMERID-45059 and PRIMERID-45064 asprimers. In both the reactions, respective wild type fragments wereadded in a molar ratio of library members present in each variablefragments. Fragment 5 and 6 are gel purified and used as templates inequimolar ratio in step 3. The primers used in the PCR reaction includePRIMERID-45057 and PRIMERID-45064. The vector PCR product was generatedusing pES1205 and primer pairs, PRIMERID-45065 and PRIMERID-45066. Bothfragment 7 and vector PCR product were gel purified and cloned togetherusing the Gibson Assembly Master Mix (New England Biolabs, Beverly,Mass.) and transformed into the cloning host E. coli Turbo (New EnglandBiolabs) according to manufacturer's instructions. 50 colonies weresequenced to determine the diversity of the library. The colonies on theagar plate were then suspended in LB media and harvested for plasmidpurification. In a similar fashion, we generated 9 specific variants ofSEQID-00407 which were altered with 9 specific amino acids, F, L, I, M,V, T, K, R, % at every variable position identified in the mutantdesign. Specific variant primers are denoted by the single letter aminoacid abbreviation in the name. All primers are listed in Table E38B.

TABLE E38B Primer sequenceGGTCATCAATCATACCACCAGTGATNTNNTNGGCNTNNTNTCCAATGAG GTTAAGAGTATTCCAAACTGGCAGTCAATTTTGGCCGAATATCACAANRNTNNTNANRGAGTTCCAATAC GGAGAAATCCTGCTCGTAATCTGGGCGTGTCGAATATCNTNANRTATNTNNTNANRGTGTCT GCGGACAAGCTAGTGACGATTTCACAATGTGATGGCTGGANTNCCTANRANRCTCTCGAACCCGAA TGGAAACGGTCATCAATCATACCACCAGTG CAGTCAATTTTGGCCGAATATCAC TCGTAATCTGGGCGTGTCGGATTTCACAATGTGATGGCTGG TGTGATATTCGGCCAAAATTGACTG GATATTCGACACGCCAGATTACGTCCAGCCATCACATTGTGAAATC ATCTGCACGCAAGGTAATCGTCAG CTGACGATTACCTTGCGTGCAGCACTGGTGGTATGATTGATGACCGGTCATCAATCATACCACCAGTGATCTTCTGGGCCTTCTGTCCAATGAG GTTAAGAGTATTCCAAACTGGGGTCATCAATCATACCACCAGTGATATTATCGGCATTATCTCCAATGAG GTTAAGAGTATTCCAAACTGGGGTCATCAATCATACCACCAGTGATGTTGTGGGCGTTGTGTCCAATGAG GTTAAGAGTATTCCAAACTGGGGTCATCAATCATACCACCAGTGATTTTTTCGGCTTTTTCTCCAATGAG GTTAAGAGTATTCCAAACTGGGGTCATCAATCATACCACCAGTGATTGGTGGGGATGGTGGTCCAATGAG GTTAAGAGTATTCCAAACTGGGGTCATCAATCATACCACCAGTGATATGATGGGCATGATGTCCAATGAG GTTAAGAGTATTCCAAACTGGGGTCATCAATCATACCACCAGTGATACAACGGGCACAACGTCCAATGAG GTTAAGAGTATTCCAAACTGGGGTCATCAATCATACCACCAGTGATTATAAGAAAGGCAAGAAAAATGAG GTTAAGAGTATTCCAAACTGGGGTCATCAATCATACCACCAGTGATTATCATCATGGCCATCACAATGAG GTTAAGAGTATTCCAAACTGGCAGTCAATTTTGGCCGAATATCACAAAGCTTCTGGGCGAGTTCCAATAC GGAGAAATCCTGCCAGTCAATTTTGGCCGAATATCACAAAGATTATCGGCGAGTTCCAATAC GGAGAAATCCTGCCAGTCAATTTTGGCCGAATATCACAAAGGTTGTGGGCGAGTTCCAATAC GGAGAAATCCTGCCAGTCAATTTTGGCCGAATATCACAAAGTTCTTTGGCGAGTTCCAATAC GGAGAAATCCTGCCAGTCAATTTTGGCCGAATATCACAAAGTGGTGGGGCGAGTTCCAATAC GGAGAAATCCTGCCAGTCAATTTTGGCCGAATATCACAAAGATGATGGGCGAGTTCCAATAC GGAGAAATCCTGCCAGTCAATTTTGGCCGAATATCACAAAGACGACAGGCGAGTTCCAATAC GGAGAAATCCTGCCAGTCAATTTTGGCCGAATATCACAAAGAAAGGAGCAGAGTTCCAATAC GGAGAAATCCTGCCAGTCAATTTTGGCCGAATATCACACATCATGGAGCAGAGTTCCAATAC GGAGAAATCCTGCTCGTAATCTGGGCGTGTCGAATATCCTTCACTATCTTCTGGATGTGTCT GCGGACAAGCTAGTGACTCGTAATCTGGGCGTGTCGAATATCATTCACTATATCATTGATGTGTCT GCGGACAAGCTAGTGACTCGTAATCTGGGCGTGTCGAATATCGTTCACTATGTTGTGGATGTGTCT GCGGACAAGCTAGTGACTCGTAATCTGGGCGTGTCGAATATCTTCCACTATTTCTTTGATGTGTCT GCGGACAAGCTAGTGACTCGTAATCTGGGCGTGTCGAATATCTGGCACTATTGGTGGGATGTGTCT GCGGACAAGCTAGTGACTCGTAATCTGGGCGTGTCGAATATCATGCACTATATGATGGATGTGTCT GCGGACAAGCTAGTGACTCGTAATCTGGGCGTGTCGAATATCACACACTATACAACGGATGTGTCT GCGGACAAGCTAGTGACTCGTAATCTGGGCGTGTCGAATATCTCCAAGTATAAAGCAAAGGTGTCT GCGGACAAGCTAGTGACTCGTAATCTGGGCGTGTCGAATATCTCCCATTATCACGCACATGTGTCT GCGGACAAGCTAGTGACGATTTCACAATGTGATGGCTGGACTTCCTGAGGAACTCTCGAACCCGAA TGGAAACGATTTCACAATGTGATGGCTGGAATTCCTGAGGAACTCTCGAACCCGAA TGGAAACGATTTCACAATGTGATGGCTGGAGTTCCTGAGGAACTCTCGAACCCGAA TGGAAACGATTTCACAATGTGATGGCTGGATTCCCTGAGGAACTCTCGAACCCGAA TGGAAACGATTTCACAATGTGATGGCTGGATGGCCTGAGGAACTCTCGAACCCGAA TGGAAACGATTTCACAATGTGATGGCTGGAATGCCTGAGGAACTCTCGAACCCGAA TGGAAACGATTTCACAATGTGATGGCTGGAACACCTGAGGAACTCTCGAACCCGAA TGGAAACGATTTCACAATGTGATGGCTGGAAAGCCTGAGGAACTCTCGAACCCGAA TGGAAACGATTTCACAATGTGATGGCTGGACATCCTGAGGAACTCTCGAACCCGAA TGGAAAC

Bacillus subtilis Strain Construction.

B. subtilis strain WB800N (MoBiTec, Göttingen, Germany) and used as theexpression host. WB800N is a derivative of a well-studied strain (B.subtilis 168) and it has been engineered to reduce protease degradationof secreted proteins by deletion of genes encoding 8 extracellularproteases (nprE, aprE, epr, hpr, mpr, nprB. vpr and wprA). B. subtilistransformations were performed according to the manufacturer'sinstructions. Approximately 5 μg of library for SEQID-00407 variantconstructs was transformed into WB800N and single colonies were selectedat 37° C. by plating on LB agar containing 5.0 μg/ml chloramphenicol(Cm5). For 9 specific variants. 1 μg of specific SEQID-00407 variant wastransformed into WB800N and single colonies were selected at 37° C. byplating on LB agar containing 5.0 μg/ml chloramphenicol (Cm5).

Bacillus subtilis Library Screening.

˜800 individual transformants of the B. subtilis SEQID-00407 librarywere used to inoculate individual, 1-ml cultures of 2×-MAL medium (20 μlNaCL 20 g/l tryptone, and 10 g/l yeast extract, 75 g/l maltose) withCm5, in deep well blocks (96-square wells). In addition to the librarystrains, a strain containing plasmid with AmyE and the SamyQ leaderpeptide was inoculated as a positive control and a strain containingplasmid with no gene of interest was inoculated as negative control.Culture blocks were covered with porous adhesive plate seals andincubated overnight in a micro-expression chamber (Glas-Col, TerreHaute, Ind.) at 37° C. and 880 rpm. Overnight cultures were used toinoculate fresh, 2×-MAL, Cm5 cultures, in deep well blocks, to astarting OD600=0.1.

Expression cultures were incubated at 37° C., 880 rpm until theOD1600=1.0 (approx. 4 hrs) at which time they were induced by addingisopropyl β-D-1-thiogalactopyranoside (IPTG) at a final concentration of1 mM and continuing incubation for 4 hrs. After 4 hrs. the celldensities of each culture was measured (OD600) and cells were harvestedby centrifugation (3000 rpm, 10 min, RT). After centrifugation, culturesupernatant was carefully removed and transferred to a new block andcell pellets were frozen at −80° C. To determine the levels of secretedprotein, 0.5-ml aliquots of the culture supernatants were filtered firstthrough a 0.45-μm filter followed by a 0.22 μm filter. The filtrateswere then assayed to determine the levels of secreted protein ofinterest (POI) by chip electrophoresis system and compared with thelevel of secretion of base construct. Briefly, samples were prepared byadding 2 μl of sample to 7 μl sample buffer, heating at 95 C for 5minutes, and then adding 35 μl of water. Analysis was completed using HTLow MW Protein Express LabChip® Kit or HT Protein Express LabChip® Kit(following the manufacturer's protocol). A protein ladder ran every 12samples for molecular weight determination (kDa) and quantification(ng/l).

SEQID-00690 and SEQID-00702 were confirmed by LC/MS/MS of the gel bandof interest. Selected hits were mixed with Invitrogen LDS Sample Buffercontaining 5% (l-mercaptoethanol, boiled and loaded on a Novex® NuPAGE®10% Bis-Tris gel (Life Technologies). After running, the gels werestained using SimplyBlue™ SafeStain (Life Technologies) and desiredbands were excised and submitted for analysis. Gel bands were washed,reduced and alkylated, and then digested with Trypsin for 4 hoursfollowed by quenching with formic acid. Digests were then analyzed bynano LC/MS/MS with a Waters NanoAcquity HPLC system interfaced to aThermoFisher Q Exactive. Peptides were loaded on a trapping column andeluted over a 75 μm analytical column at 350 nL/min; both columns werepacked with Jupiter Proteo resin (Phenomenex). The mass spectrometer wasoperated in data-dependent mode, with MS and MS/MS performed in theOrbitrap at 70,000 FWHM resolution and 17,500 FWHM resolution,respectively. The fifteen most abundant ions were selected for MS/MS.The resulting peptide data were searched using Mascot against therelevant host database with relevant variant protein sequence appended.

Diluted overnight cultures were used as inoculum for LB broth culturescontaining Cm5. These cultures were grown at 37 C until they reached logphase. Aliquots of these cultures were mixed with glycerol (20% finalconcentration) and frozen at −80° C. The top 30 hits are then purifiedusing Instagene matrix (Biorad, USA) and amplified usingCTTGAAATTGGGAACGGGATTC and GTATAAACTTTTCAGTTGCAGAC, and sequenced usingthe same primers to identify the SEQID-00407 variant sequence.

Bacillus subtilis Secretion Library Analysis.

All the secreted variants of SEQID-00407 (SEQIDs 45002-45028) wereanalyzed to determine if there were any position specific biases in theamino acids present in the secreted variants, relative to the expectedposition specific biases present in the initial genetic library. To thisend, an exact binomial test was performed for each amino acid at eachposition to determine the likelihood that the observed number of eachamino acid was significantly (p<0.05) more or less than expected bychance. Table E38 C shows the p-values of this single tailed test, wherethose highlighted elements have p values <0.05. Note that aside fromwild type values, which were all significantly higher than expected, allother significant different amino acid frequencies were less thanexpected. The expected position specific amino acid biases are shown inTable E38D, and were found by sequencing 47 randomly selected variantsafter the library had been constructed and transformed into E. coli. Itwas assumed that all positions designed to be an X effectively sampledfrom the same distribution of L, 1, V, F, and M codons (i.e., for all Xpositions, there were no position specific amino acid biases). As such,the observed counts of each amino acid were aggregated across positionsto determine the expected amino acid likelihoods for all X positions. Asimilar assumption was made for all positions designed to be a Z. As canbe seen in Table E38 C, in addition to the strong bias toward the wildtype sequence at each position, there are a number of different aminoacids that were observed significantly less than expected, indicating abias away from those amino acids at that position in the secretedlibrary. This data provides additional information for the design ofspecific, rationally designed variants with specific mutations at eachposition. As an example, to enrich a secreted variant in leucine,positions 241 and 291 may be less desired choices. Alternatively, toenrich a secreted variant in valine, positions 149, 241, 242, 291, 294,295, and 389 may be less desired choices.

TABLE E38C Single tailed binomial test p-values assessing positionspecific amino acid biases in secreted variants of SEQID-450001

TABLE E38D Position specific, expected amino acid likelihoods in theconstructed SEQID-450001 library X Z L 30.2% — I 12.3%  9.7% V 36.4% — F 6.7% — M 10.7% 12.2% T — 18.3% K — 17.9% R — 36.2% Wt  3.7%  5.7%

Bacillus subtilis Expression Testing of Specific Variants.

Three separate colonies of B. subtilis expression strains were used toinoculate 1-ml of 2×-MAL medium (20 g/l NaCl, 20 g/l tryptone, and 10g/l yeast extract, 75 g/l maltose) with Cm5, in deep well blocks(96-square wells). Culture blocks were covered with porous adhesiveplate seals and incubated overnight in a micro-expression chamber(Glas-Col, Terre Haute, Ind.) at 37° C. and 880 rpm. Overnight cultureswere used to inoculate fresh, 2×-MAL, Cm5 cultures, in deep well blocks,to a starting OD600=0.1. These expression cultures were incubated at 37°C., 880 rpm until the OD600=1.0 (approx. 4 hrs) at which time they wereinduced by adding isopropyl β-D-1-thiogalactopyranoside (IPTG) at afinal concentration of 0.1 M and continuing incubation for 4 hrs. After4 hrs, the cell densities of each culture was measured (OD600) and cellswere harvested by centrifugation (3000 rpm, 10 min, RT). Aftercentrifugation, culture supernatant was carefully removed andtransferred to a new block and cell pellets were frozen at −80° C. Todetermine the levels of secreted protein. 0.5-ml aliquots of the culturesupernatants were filtered first through a 0.45-μm filter followed by a0.22 μm filter. The filtrates were then assayed to determine the levelsof secreted protein of interest (POI) by chip electrophoresis. Briefly,samples were prepared by adding 2 μl of sample to 7 μl sample buffer,heating at 95 C for 5 minutes, and then adding 35 μl of water. Analysiswas completed using HT Low MW Protein Express LabChip® Kit or HT ProteinExpress LabChip® Kit (following the manufacturer's protocol). A proteinladder ran every 12 samples for molecular weight determination (kDa) andquantification (ng/μl).

SEQID-45025, SEQID-45026, SEQID-45027, and SEQID-45028 were confirmed byLC/MS/MS of the gel band of interest. Selected hits were mixed withInvitrogen LDS Sample Buffer containing 5% 0-mercaptoethanol, boiled andloaded on a Novex®% NuPAGE® 10% Bis-Tris gel (Life Technologies). Afterrunning, the gels were stained using SimplyBlue™ SafeStain (LifeTechnologies) and desired bands were excised and submitted for analysis.Gel bands were washed, reduced and alkylated, and then digested withTrypsin for 4 hours followed by quenching with formic acid. Digests werethen analyzed by nano LC/MS/MS with a Waters NanoAcquity HPLC systeminterfaced to a ThermoFisher Q Exactive. Peptides were loaded on atrapping column and eluted over a 75 μm analytical column at 350 nL/min;both columns were packed with Jupiter Proteo resin (Phenomenex). Themass spectrometer was operated in data-dependent mode, with MS and MS/MSperformed in the Orbitrap at 70,000 FWHM resolution and 17,500 FWHMresolution, respectively. The fifteen most abundant ions were selectedfor MS/MS. The resulting peptide data were searched using Mascot againstthe relevant host database with relevant variant protein sequenceappended.

Amylase Activity Assay for Engineered Polypeptides.

One of the engineered polypeptides were tested to demonstrate enzymaticactivity. SEQID-00407 is an a-amylase in Bacillus subtilis that has theactivity of breaking down polysaccharides, such as starch, intomonosaccharides or disaccharides. To demonstrate that the SEQID-00690has retained enzymatic activity, Bacillus subtilis secreting the enzymewere plated onto agar plates containing starch. If there is enzymaticactivity, the secreted enzyme will breakdown the starch and uponstaining by iodine, there will be a halo surrounding the Bacillussubtilis colonies. 1% starch plates were made by combining 25 g LuriaBroth-Miller, 10 g starch, 15 g bacteriological agar, and 1 L water. 10mM IPTG was added to the starch plates after the agar has solidified.Single colonies of Bacillus subtilis strains expressing the mutantpolypeptides were inoculated in 5 ml LB at 370(for 4 hours and 50 μl ofthe liquid culture were spotted at the center for the starch plates.After 20 hours of growth and induced secretion, 10% iodine was added tothe starch plates to stain for starch. When SEQID-00690 was plated onthe starch plates, the enzyme is secreted abd creates a large haloaround the cells, similar to wild-type strain, and much larger than thenegative control strain, which expresses the empty vector without theenzyme. Table E38E quantifies the area of the halos relative to the areaof the cells. From the data shown, we demonstrated the engineering ofsecreted nutritive polypeptide enriched in essential amino acids whichretains enzymatic activity.

TABLE E38E Quantified area of cells, halos, and their differencesmeasured in in2. Protein Cell Area (in²) Halo Area (in²) Halo/Cell Noprotein control 0.413 0.600 1.45 Wild-type 1.270 2.246 1.77 SEQID-006900.469 1.234 2.63

Example 39 Determination of Muscle Protein Fractional Synthesis Rate inHuman Subjects Following Oral Consumption of Leucine-Enriched NutritivePolypeptides

Oral ingestion of leucine or leucine-containing proteins stimulatesmuscle protein synthesis (Layman & Walker, 2006, The Journal ofnutrition: 136: 319-323). Many of the leucine-enriched nutritivepolypeptides described herein are highly water soluble and readilydigested and absorbed in human subjects. The pharmacokinetics of aminoacids as delivered via nutritive polypeptides and their effect on muscleprotein synthesis are described here.

Effects of the leucine-enriched nutritive polypeptides on muscle proteinsynthesis were measured in apparently healthy subjects. Twelve (12)apparently healthy subjects (average height: 1.7 m, weight: 78.5 kg,age: 56.2, and BMI: 26.8) between the ages of 50 and 70 were randomlyassigned in a single-blinded manner to a sequence of treatments. Onegroup of six received formulations of SEQID-105 and 90% whey proteinisolate (WPI) control, and the other group received SEQID-363 and 90%whey protein isolate control. The treatments were staggered such thateach individual received 35 grams of each nutritive polypeptideformulation on separate days (2-3 days apart) to allow for washout ofthe initial formulation. Each subject served as their own control in thewithin-subject cross-over comparison.

Subjects were excluded from the study if they met any of the followingexclusion criteria: History of diabetes. History of malignancy in theprevious 6 months. Prior gastrointestinal bypass surgery (Lapband,etc.). Chronic inflammatory condition or disease (Lupus, HIV/AIDS,etc.). Known sensitivity or allergy to whey protein, mold spores orfungi. Do not refrain from eating animal proteins during theirparticipation in this study. Cannot refrain from consuming protein oramino acid supplements during their participation in this study. Cannotrefrain from resistance training during the study period. Currentlyparticipating in another research study with an investigational product.Hemoglobin less than 9.5 mg/dl at the screening visit. Concomitant useof corticosteroids or testosterone replacement therapy (ingestion,injection, or transdermal). Any other diseases or conditions that wouldplace the subject at increased risk of harm if they were to participate,at the discretion of the medical staff.

All subjects were asked to maintain their current dietary habits,maintain their activities of daily living, and to not participate in anyresistance exercise during the study.

The anabolic effect of each nutritive formulation was measured using thefractional rate of muscle protein synthesis (FSR) (Smith, Villareal, &Mittendorfer, 2007, American journal of physiology—Endocrinology andmetabolism: 293: E666-E671). Research procedures included venous blooddraws and vastus lateralis muscle biopsies during a primed, constantinfusion of L-[ring-d5]-phenylalanine (Cambridge Isotope Laboratories,Tewksbury, Mass.). The fractional rate of muscle protein synthesis (FSR)was measured by muscle biopsies during a primed, constant infusion ofL-[ring-d5]-phenylalanine. Specifically, the fractional rate of muscleprotein synthesis (FSR) was measured in fasted human subjects after anovernight fast (>8 hrs) using the stable isotope tracer incorporationtechnique from vastus lateralis muscle biopsies performed 2, 4, and 7hrs after initiating stable isotope tracer infusion. Blood samples werealso collected at specified time points after the beginning of stableisotope tracer infusion (i.e. 2, 3, 4, 4+30, 5, 5+30, 6, 6+30, and 7hrs) to assess changes in amino acid concentrations.

For each subject, on the morning of the study and after an overnightfast (8 hrs), an 18-22 gauge polyethylene catheter was inserted intoeach arm. One catheter was inserted into a distal vein for heated bloodsampling to obtain a background blood sample (5 ml), and another intothe forearm for infusion of the stable isotope tracers. After insertionof peripheral catheters, a primed (5.04 μmol/kg), constant (0.084μmol/kg/min) infusion of the stable isotope (GRAS substance)ring-d5-phenylalanine was started. Stable isotopes were obtained fromCambridge Isotope Laboratories (Tewksbury, Mass.) and were tested forsterility and pyrogenicity (by CIL and the preparingpharmacy—PharmaCare). Prior to infusion, the tracer was reconstitutedwith sterile saline. The stable isotope was filtered during infusionthrough a sterile 0.22 micron (Millipore) filter placed in the infusionline.

Blood samples (5 ml) were collected in serum separator tubes atspecified time points after the beginning of isotope infusion (2, 3, 4,4+30, 5, 5+30, 6, 6+30, and 7 hrs). About 60 ml of blood was drawnduring the entire study, and this volume was replaced with salineinfused with a stable isotope tracer.

Muscle biopsies from the vastus lateralis were performed at 2, 4, and 7hrs of tracer infusion. After the biopsy at 4 hr, the nutritive proteinformulation was administered orally. All muscle biopsies were performedunder local anesthesia (using sterile 1% lidocaine, without epinephrine)for normal pain management and strict sterile procedures. Prior to eachmuscle biopsy, skin was cleaned using a sterile skin preparation kitBetadine), and the skin and tissue below was injected with localanesthetic (Lidocaine) to minimize pain.

Through a small incision (about 1 cm), a 5 mm Bergström needle “0” wasadvanced into the muscle and suction applied. A piece of the muscle wasthen removed with the needle (approximately 50-100 mg). The skin wasthen cleansed, edges approximated with ¼ inch×1.5 inch adhesiveSteri-strips, and a transparent, breathable film dressing (Tegaderm) wasapplied to the site. Firm pressure was maintained until bleeding at thesite ceased. To minimize the risk of infection and bruising, anantibiotic ointment and pressure dressing (with self-adhesive elasticbandage) was applied, respectively, by the medical staff before thesubject was released.

FSR, measured in (%/hr), was calculated as follows:

${{FSR} = {\left\lbrack \frac{E_{P_{1}} - E_{P_{2}}}{E_{m}} \right\rbrack*\frac{1}{t}*60*100}},$

where enrichments (EP1, EP2, and Em) are expressed as mole percentexcess (MPE) and calculated as the ratio of labeled phenylalanine tracerto unlabeled phenylalanine tracee (TTR), once the tracer concentrationhas plateaued. EP1 and EP2 are the enrichments of boundring-2H5-phenylalanine in the first and second biopsies (or second andthird), respectively, and Em is the mean value of the enrichments ofring-2H5-phenylalanine in the intracellular pool. “t” is the time inminutes elapsed between 1st and 2nd muscle biopsy in min (or between thesecond and third). Constant conversion factors of 60 min/hr and 100 wereused to express FSR in percent per hour. Outcome variables (muscleprotein synthesis and blood amino acid concentrations) were analyzed viapaired t-tests. Statistical significance was established a priori atP<0.05 and trends were accepted as 0.051<P<0.10.

Tables E39A-C show the calculated FSR data for each subject before andafter an acute, oral dose of each nutritive protein formulation, andFIG. 56 shows the change in average FSR. The data shown is themean+/−standard error of the mean. Note that the fasted FSR value fromsubject 3 in the WPI group had a very elevated FSR, inconsistent withnormal fasted values, with a z-value of 2.85. A two-tailed grubbs'outlier test indicated that it was a significant (p<0.05) outlier and itwas removed when calculating the mean and standard error as shown inFIG. 56.

TABLE E39A Subject WPI FSR (hr⁻¹) ID Fasted Fed 1 0.00023651 0.000721082 0.00041336 0.00037967 3 0.00168551 0.00022099 4 0.00032137 0.001124585 0.00064807 0.0005574 6 0.00078224 0.00133908 7 0.00029799 0.00058582 80.00063563 0.0007537 9 0.00043453 0.000653 10 0.0006604 0.00088189 110.00056282 0.00067366 12 0.00040945 0.00070602

TABLE E39B Subject SEQID-363 FSR (hr⁻¹) ID Fasted Fed 1 0.000408820.00106664 2 0.00090652 0.00040036 3 0.00040061 0.00094592 4 0.000788520.00082819 5 0.00057147 0.00038021 6 0.00054359 0.00047435

TABLE E39C Subject SEQID-105 FSR (hr⁻¹) ID Fasted Fed 7 0.000377240.00090154 8 0.00041119 0.00047965 9 0.00043875 0.00075389 10 0.000391120.00032007 11 0.00049953 0.00088001 12 0.00022427 0.00085157

Paired t-tests comparing the fasted and fed response of each groupindicate that the fed response in the WPI treated subjects issignificantly different from the fasted response when subject 3 isremoved. (p=0.007), consistent with previous studies examining the FSRresponse to WPI (Paddon-Jones, D., Sheffield-Moore, M., Katsanos C. S.,Xiao-Jun Z., Wolfe. R. R. Differential stimulation of muscle proteinsynthesis in elderly humans following isocaloric ingestion in aminoacids or whey protein. Exp. Gerontol. (2006) 41: 215-219). If subjectthree is included, the difference loses significance (p=0.45). Thefasted and fed FSR response in the SEQID-105 fed group are significantlydifferent (p=0.04), but the fasted and fed FSR response in the SEQID-363fed group are not significantly different (p=0.68).

Example 40 Oral Pharmacokinetics of Formulations Containing NutritivePolypeptides

The anabolic response to protein ingestion is predicated on the deliveryof essential amino acids. The purpose of this study was to examine thechanges in plasma amino acid concentrations in response to variousproteins over a period of 240 minutes. Four apparently healthy subjectsbetween the ages of 18 and 50 were randomly assigned in a double-blindedmanner to a sequence of treatments, receiving 20 grams of either wheyprotein isolate or SEQID-105 orally, in a volume of 170 ml. Subjectswere fasted overnight (>8 hrs) before oral pharmacokinetic study. Venousblood samples were collected at specified time points (i.e. 0, 15, 30,60, 90, 120, 150, 180, 210 and 240 minutes) following the oral ingestionof nutritive polypeptide to assess changes in plasma amino acidconcentrations. Plasma amino acid concentrations were quantified byQuest Diagnostics or Laboratory Corporation of America.

FIGS. 57-60 show the plasma time course of each measured amino acid andthe aggregate groups, essential amino acids (EAA), branched chain aminoacids (BCAA), and total amino acids (TAA), for WPI and SEQID-105.

Using a 1-way ANOVA test to assess significant differences in plasmaamino acid levels across the time points measured, for WPI, these dataindicate that there are significant differences across time for Asn,lie, Leu, Lys. Met, Phe, Pro, Trp, Tyr, EAA. BCAA, and TAA (p<0.05).

Using a 1-way ANOVA test to assess significant differences in plasmaamino acid levels across the time points measured, for a nutritiveformulation of SEQID-105, these data indicate that there are significantdifferences across time for Arg, Asn, Asp, Glu, Gly, His, Ile, Leu, Lys,Met, Phe, Ser, Tyr, Val, EAA, BCAA, and TAA (p<0.05).

FIGS. 61-63 show the integrated area under the curve (AUC) of eachmeasured amino acid as well as the aggregate groups, essential aminoacids (EAA), branched chain amino acids (BCAA), and total amino acids(TAA), for WPI and SEQID-105.

Using a t-test to compare the AUCs of each amino acid or amino acidgroup between WPI and SEQID-105, there are significant differences inthe Asp (p=0.01), His (p=0.04), Leu (0.023). Met (0.002), Phe (0.04).Pro (p<0.01), Ser (p=0.03), and Trp (p=0.002) responses.

In another study, a 35 gram dose of SEQID-105 and WPI was given orallyin 100 ml and 1151 ml, respectively, to six, apparently healthy subjectsbetween the ages of 18 and 50. FIGS. 64-67 show the plasma time courseof each measured amino acid and the aggregate groups, essential aminoacids (EAA), branched chain amino acids (BCAA), and total amino acids(TAA), for WPI and SEQID-105.

Using a 1-way ANOVA test to assess significant differences in plasmaamino acid levels across the time points measured, for WPI, these dataindicate that there are significant differences across time for Arg,Asn, Asp, Gln, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val,EAA, BCAA, and TAA (p<0.05).

Using a 1-way ANOVA test to assess significant differences in plasmaamino acid levels across the time points measured, for a nutritiveformulation of SEQID-105, these data indicate that them are significantdifferences across time for

Arg, Asn, Asp, Glu, His, Ile, Ley, Lys, Met, Phe, Ser, Thr, Trp, ValEAA, BCAA, and TAA (p<0.05).

FIGS. 68-70 show the integrated area under the curve (AUC) of eachmeasured amino acid as well as the aggregate groups, essential aminoacids (EAA), branched chain amino acids (BCAA), and total amino acids(TAA), for WPI and SEQID-105 dosed at 35 g.

Using a two-tailed, unequal variance t-test to compare the AUCs of eachamino acid or amino acid group between WPI and SEQID-105, there aresignificant differences in the Asn (p=0.006), His (p=0.01), Ile(p=0.03), Lys (p=0.02), Met (p<0.001), Phe (p<0.001), Pro (p=0.002), Ser(p=0.005), Thr (p=0.004), Trp (p<0.001), Tyr (p=0.003), and Val(p=0.012) responses.

In another study examining the pharmacokinetics of amino acid deliveryvia nutritive polypeptides, three apparently healthy subjects betweenthe ages of 18 and 50 were randomly assigned in a double-blinded mannerto a sequence of treatments, receiving 20 grams of either whey proteinisolate or SEQID-363 orally. Subjects were fasted overnight (>8 hrs)before oral pharmacokinetic study. Venous blood samples were collectedat specified time points (i.e. 0, 15, 30, 60, 90, 120, 150, 180, 210 and240 minutes) following the oral ingestion of nutritive polypeptide toassess changes in plasma amino acid concentrations. Plasma amino acidconcentrations were quantified by Quest Diagnostics or LaboratoryCorporation of America.

FIGS. 71-74 show the plasma time course of each measured amino acid andthe aggregate groups, essential amino acids (EAA), branched chain aminoacids (BCAA), and total amino acids (TAA), for WPI and SEQID-363.

Using a 1-way ANOVA test to assess significant differences in plasmaamino acid levels across the time points measured, for WPI, these dataindicate that there are significant differences across time for Gin,Ile. Leu, Lys, Phe, Ser, Tyr, Val, EAA, BCAA, and TAA (pr<0.05).

Using a 1-way ANOVA test to assess significant differences in plasmaamino acid levels across the time points measured, for SEQID-363, thesedata indicate that there are no significant differences across time(p<0.05).

Example 41 Chronic Treatment of Sarcopenia and Loss of Physical Functionin Elderly Frail Subjects Using Nutritive Polypeptides

Supplementation of leucine or leucine-containing proteins improve musclemass build-up after exercise and maintain skeletal muscle mass duringlong-term disuse (Layman & Walker, 2006, The Journal of nutrition: 136:319-323). Nutritive polypeptides enriched in leucine and essential aminoacids are described herein. Elderly, frail subjects are randomlyassigned in a double blind manner to a specific treatment group: acontrol group receiving an isocaloric control or one of 3 dose rangingtreatment arm receiving 3 times daily a dose of 15, 30, or 40 grams of anutritive polypeptide formulation for 30 days. Enrolled subjects areprovided with a control diet based upon individual's body mass index(BMI) and physical activities throughout the trial period. Food andcalorie intakes are recorded. Enrolled subjects maintain their regulardaily activities. Daily physical activities and calorie consumption aremeasured by a physical activity tracker (FitBit Flex wrist band). Leanbody mass is measured by MRI (Miller. M. J., et al. “Assessment anddefinition of lean body mass deficiency in the elderly.” Europeanjournal of clinical nutrition (2014)) or dual-energy X-rayabsorptiometry (DEXA; Nielsen, Palle Kjrerulff, Jorgen Ladefoged, andKlaus Olgaard. “Lean body mass by Dual Energy X-ray Absorptiometry(DEXA) and by urine and dialysate creatinine recovery in CAPD andpre-dialysis patients compared to normal subjects.” Adv Perit Dial 10(1994): 99-103.) on day 1 (prior to nutritive polypeptide dosing) andday 31 after treatment has concluded to assess the change of skeletalmuscle mass. Physical function is also assessed at the start and end ofthe treatment period using the short physical performance battery score(Volpato, Stefano, et al. “Predictive value of the Short PhysicalPerformance Battery following hospitalization in older patients.” TheJournals of Gerontology Series A: Biological Sciences and MedicalSciences 66.1 (2011): 89-96.), measures of gait speed. 6 minute walktest (6MWT), and the timed up and go test (TUGS; Podsiadlo, D;Richardson, S. “The timed ‘Up & Go’: A test of basic functional mobilityfor frail elderly persons”. Journal of the American Geriatrics Society(1991) 39: 142-8). The absolute and percent change in lean body mass aswell as SPPB score, gait speed, 6MWT, and TUGS, from baseline iscompared across treatment arms and relative to control to assesstreatment efficacy.

Example 42 Oral Pharmacokinetics of Formulations Containing NutritivePolypeptides Deficient in Methionine

The purpose of this study was to examine the changes in plasma aminoacid concentrations in response to a methionine deficient nutritiveprotein over a period of 240 minutes. Four apparently healthy subjectsbetween the ages of 18 and 50 were randomly assigned in a double-blindedmanner to a sequence of treatments, receiving 20 grams of SEQID-426orally, in a volume of 170 ml. Subjects were fasted overnight (>8 hrs),and the following morning venous blood samples were collected atspecified time points (i.e. 0, 15, 30, 60, 90, 120, 150, 180, 210 and240 minutes) after the oral ingestion of nutritive polypeptide to assesschanges in plasma amino acid concentrations. Plasma amino acidconcentrations were quantified by Quest Diagnostics or LaboratoryCorporation of America.

FIGS. 75-78 show the plasma time course of each measured amino acid andthe aggregate groups, essential amino acids (EAA), branched chain aminoacids (BCAA), and total amino acids (TAA), for SEQID-426.

Using a 1-way ANOVA test to assess significant differences in plasmaamino acid levels across the time points measured, for SEQID-426, thesedata indicate that there are significant differences across time for Gluand EAA (p<0.05). A Dunnett multiple comparison test examining theplasma EAA time course further indicates that the plasma EAA levels atthe 30 and 60 min. time points are significantly different from thebasal levels at time 0 min. Methionine shows no significant change overtime.

Example 43 Selection of Nutritive Polypeptides for Increasing RenalFunction and Treatment and Prevention of Renal Diseases

Nutritive polypeptides are selected from a database of edible proteinsas described herein. As a result of inadequate metabolic and nutritionalstatus high mortality and morbidity rates remain prevalent in patientssuffering from chronic kidney disease (CKD, particularly in those withend-stage renal disease (ESRD) receiving dialysis. This altered status,deemed protein energy wasting (PEW), can be caused by inadequate dietaryprotein intake and utilization and has a significant effect on patientmortality rate. Dialysis depletes the body of amino acids and thecompromised kidneys alter amino acid homeostasis in the human body. PEWcan result in loss of muscle and protein stores compounding the effectsof renal disease. Nutritive polypeptide compositions are useful fortreatment of renal diseases. Also, CKD patients are known to haveabnormal amino acid profiles in serum, in particular, essential aminoacids (EAAs) and branched chain amino acids (BCAAs). Kim et. al. reportlower serum BCAAs levels in ESRD dialysis patients compared to a controlgroup. More specifically, lower levels of serine, tyrosine and lysine aswell as the BCAAs-valine, leucine and isoleucine have been reported(Kim. D. H. Kor. Journ. Int. Med. 1998, 13(1): 33-40). Therefore.BCAA-enriched nutritive polypeptides and/or EAA-enriched nutritivepolypeptides are of particular utility for patients with CKD.

Supplementation of BCAAs in the diet can improve the nutritional statusand appetite of dialysis patients. (Hiroshige, K. Nephr. Dial.Transplant. 2001, 16:1856-62). Levels of BCAAs were normalized by 12g/day oral supplements. Nutritive polypeptides high in BCAAs are aneffective treatment for patients compromised by renal disease. PEW canbe remedied by restoring the specific amino acids lost by dialysis anddiminished metabolic function by nutritive polypeptide administrationwhile diminishing stress on an already compromised patient. A nutritivepolypeptide selected for improving the status of ESRD patients,particularly those with PEW, delivers optimal combinations of aminoacids at a beneficial quantity. Specifically, a nutritive polypeptidehigh in BCAAs satisfies these requirements. The nutritive polypeptideoptionally is low in glutamine and glutamic acid content, since patientswith renal disease do not efficiently excrete ammonia, a by-product ofglutamic acid and glutamine metabolism. Accumulation of ammonia in theblood, also known as hyperammonemia, is a dangerous condition that maylead to death (Sacks, G. S. Ann. Pharmacol. 1999, 33:348-354).

Uremic toxicity, where excess nitrogenous waste products exist incirculation often occurs in CKD and, must be monitored. CKD patients aresometimes placed on a low protein diet to prevent uremic toxicity. Urea,the main nitrogenous metabolite from ingestion of protein, may or maynot be toxic alone, and can serve as an indicator of accumulation ofother toxins as a consequence of altered renal function. Thus, anutritive polypeptide is able to deliver amino acids optimally to meet asubject's nutritional needs while diminishing risks of these sideeffects. A high BCAA protein satisfies these requirements. Where someESRD patients are placed on a low protein diet, dialysis patients areplaced on a high protein diet due to loss of amino acids that occurduring the dialysis process. Hyperphosphatemia is a complication of apoorly optimized high protein diet, where high phosphorous levels fromfood can become toxic in individuals with CKD (Mandayam, S. Nephrology.2006, 11:53-57). Even mild increases in serum phosphorous levelsincreased mortality rates in CKD patients (Kestenbaum, B. J Am. Soc.Nephrol. 2005, 16: 520-28). A nutritive polypeptide is advantageous inCKD, as it counteracts the loss of amino acids, while sparing thekidneys of extraneous dietary phosphorous.

An exemplary list of nutritive polypeptides from the edible databasedescribed herein useful for treatment of renal disease are summarized inTable E43A. These are high in BCAA content and optionally low inglutamine and glutamic acid content.

TABLE E43A SEQID EAA BCAA Q E SEQID-03580 0.55 0.24 0.00 0.00SEQID-03636 0.65 0.24 0.00 0.00 SEQID-03629 0.56 0.31 0.06 0.04SEQID-03441 0.57 0.29 0.02 0.06 SEQID-03620 0.54 0.28 0.04 0.03SEQID-03468 0.62 0.25 0.00 0.04 SEQID-03553 0.47 0.27 0.00 0.06SEQID-03535 0.54 0.28 0.04 0.03 SEQID-03476 0.50 0.25 0.04 0.00SEQID-03582 0.54 0.23 0.02 0.00

TABLE E43B SEQID EAA BCAA Q E SEQID-00162 0.64 0.53 0.02 0.02SEQID-00134 0.58 0.46 0.00 0.02 SEQID-00169 0.60 0.43 0.02 0.02SEQID-00166 0.65 0.46 0.03 0.03 SEQID-00561 0.68 0.36 0.02 0.03SEQID-00175 0.63 0.38 0.02 0.04 SEQID-00137 0.64 0.39 0.00 0.07SEQID-00132 0.60 0.41 0.02 0.07 SEQID-00195 0.52 0.36 0.00 0.07SEQID-00194 0.54 0.36 0.00 0.07

Example 44 Effect of Amino Acids and Nutritive Polypeptides on RenalFibrosis In Vitro

Efficacy of high-BCAA nutritive polypeptides is demonstrated by using anin vitro assay modeling kidney disease, which utilizes the pericyte tomyofibroblast transition that occurs during kidney fibrosis. Fibrosisreflects pathology observed in end-stage renal failure. Myofibroblastformation is studied by quantitative polymerase chain reaction (qPCR)and Western Blot (WB) in cultured kidney cells (Wu, C. F. Am. Journ.Path. 2013, 182(1): 118-31). Normal kidney pericytes are incubated withTGF-β1 to induce the transition to myofibroblasts and a-smooth muscleactin (α-SMA) is used as a marker of myofibroblast differentiation.Incorporation of nutritive polypeptides into the assay as digests orfree amino acid blends is the sole amino acid source in amino acid-freeserum in cell culture as opposed to 20% fetal bovine serum. (Kuncio, G.S. Kidn. Int. 1991, 39:550-556).

Example 45 Treatment of Chronic Kidney Disease with NutritivePolypeptides in Rodents

Efficacy of high-BCAA nutritive polypeptides is demonstrated using a ratmodel of renal disease by 5/6 nephrectomy (Gao, X. Kidney Int. 2011,79(9): 978-996. Nutritive polypeptides high in BCAAs and optionally lowin glutamine and glutamic acid are orally administered to supplement alow-protein diet or a protein-free diet using low-protein andhigh-protein diet controls. Body weight, blood urea levels and renallesions are measured to demonstrate improved parameters compared to thecontrols.

Example 46 Treatment of Chronic Kidney Disease with NutritivePolypeptides in Humans

A nutritive polypeptide high in BCAAs and low in glutamate and glutamineis selected and orally dosed to humans for improvement of symptomsresulting from ESRD. By administering a nutritive polypeptide for 2, 3,4, 5 or 6 months or control and measuring parameters such as dry bodyweight, body mass index, body fat percentage, lean body mass, dietaryprotein intake, dietary caloric intake and plasma levels of urea,ammonia, phosphorous, albumin and BCAAs, nutritive polypeptides efficacyare assessed. A nutritive polypeptide for nutritional support isbeneficial as concern exists for stress on the kidney by supply ofexcess protein.

Example 47 Selection of Nutritive Polypeptides for the Treatment of UreaCycle Disorders

Urea cycle disorder (UCD) patients are treated or symptoms prevented byadministration of nutritive polypeptides. The urea cycle is the mainnitrogenous waste disposal pathway in humans. UCD is a hereditarydisorder caused by deficiency of one or more enzymes in the cycle,ultimately resulting in hyperammonemia. UCD patients present low BCAAserum levels. (Boneh. A. Mol. Genet. Metab. 2014. S1096-7192).Disruption of the normal urea cycle causes diminished synthesis ofarginine, normally a nonessential amino acid (Leonard, J. V. Journ.Pediatrics. 2001, 138(1):S40-45). Arginine plays a major role in theurea cycle. The synthetic pathway of arginine interacts closely withurea cycle enzymes in the liver and kidneys and is made from ornithinevia citrulline (Barbul A. J Parenter Enteral Nutr. 1986, 10: 227-238).Citrulline and ornithine have been supplemented in UCD patients;however, they are not found in natural proteins and are not present innutritive polypeptides. A nutritive polypeptide indicated for urea cycledisorders contains high levels of BCAAs and arginine. Supplementation ofglutamine and glutamic acid produces the nitrogenous waste productammonia, so a nutritive polypeptide useful for UCD is generally low inthese amino acids. A nutritive polypeptide provides an optimized therapyfor UCD patients, as it can deliver essential amino acids such as theBCAAs, as well as arginine, without delivering excess amino acids.

An exemplary list of nutritive polypeptides from the edible databaseuseful for the treatment of urea cycle disorders are summarized in TableE47A. These are high in BCAA and arginine content and low in glutamineand glutamic acid content.

TABLE E47A SEQID EAA BCAA Q R E SEQID-03551 0.48 0.16 0.02 0.36 0.00SEQID-03554 0.43 0.24 0.04 0.25 0.01 SEQID-03568 0.44 0.23 0.04 0.260.01 SEQID-03434 0.43 0.21 0.04 0.27 0.01 SEQID-03468 0.62 0.25 0.000.21 0.04 SEQID-03560 0.43 0.23 0.04 0.24 0.01 SEQID-03578 0.37 0.190.06 0.35 0.03 SEQID-03593 0.39 0.19 0.06 0.34 0.03 SEQID-03435 0.400.22 0.06 0.32 0.03 SEQID-03582 0.54 0.23 0.02 0.18 0.00

An exemplary list of nutritive polypeptides from the expressed databasedescribed herein useful for the treatment of renal disease aresummarized in table E47B.

TABLE E47B SEQID EAA BCAA Q R E SEQID-00134 0.58 0.46 0.00 0.06 0.02SEQID-00162 0.64 0.53 0.02 0.00 0.02 SEQID-00166 0.65 0.46 0.03 0.040.03 SEQID-00169 0.60 0.43 0.02 0.00 0.02 SEQID-00636 0.47 0.23 0.020.22 0.04 SEQID-00195 0.52 0.36 0.00 0.08 0.07 SEQID-00194 0.54 0.360.00 0.08 0.07 SEQID-00540 0.41 0.21 0.03 0.23 0.05 SEQID-00132 0.600.41 0.02 0.05 0.07 SEQID-00043 0.57 0.41 0.02 0.08 0.09

Example 48 Effect of Amino Acids and Nutritive Polypeptides on UreaCycle Disorders In Vitro

Efficacy of high-BCAA nutritive polypeptides for UCD is demonstrated byusing an in vitro liver model of UCD assessing viability ofmurine-derived embryonic stem cells. Ornithine has been shown toincrease cell viability (Tamai, M. Amino Acids. 2013.45:1343-1351).Briefly, hepatocytes derived from mice are cultured. Nutritivepolypeptides as digests or blends of free amino acids in the cellculture medium protected the cells against NH₄+ induced hepatocytedeath. This is due to enhanced enzymatic conversion of ammonium to ureain the urea cycle. Urea was quantified in the media by a QuantiChrom™Urea Assay Kit (BioAssay Systems, CA) and ammonia quantified by AmmoniaTest Wako (Wako, Osaka, Japan). Cell viability was measured by a CellCounting Kit (Dijindo Laboratories Kumamoto, Japan). A nutritivepolypeptide intended for UCD therapy is supplemented against anL-ornithine control and cell viability and urea and ammoniaconcentrations quantified.

Example 49 Treatment of Urea Cycle Disorders with Nutritive Polypeptidesin Rodents

Efficacy of high-BCAA nutritive polypeptides for UCD is demonstrated byusing a mouse gene knockout study. DeMars et. al. describe a mutationthat reduces activity of the urea cycle enzyme ornithinetranscarbamylase—a common deficiency in UCD patients (DeMars, R. Proc.Natl. Acad. Sci. 1976, 73: 1693-1697). Oral supplementation of high BCAAand arginine nutritive polypeptides in a mouse diet shows normalizationof serum BCAA and arginine profiles in mice compared to the controldiet.

Example 50 Treatment of Urea Cycle Disorders with Nutritive Polypeptidesin Humans

Human oral administration of nutritive polypeptides high in BCAAs andarginine and low in glutamine and glutamic acid is performed andmeasurements are made as described herein. Specifically, byadministering a nutritive polypeptide for 2, 3, 4, 5 or 6 months orcontrol and measuring parameters such as dry body weight, body massindex, body fat percentage, lean body mass, dietary protein intake,dietary caloric intake and plasma levels of urea, ammonia, phosphorous,albumin and BCAAs, nutritive polypeptides efficacy are assessed.

While the invention has been particularly shown and described withreference to a preferred embodiment and various alternate embodiments,it will be understood by persons skilled in the relevant art thatvarious changes in form and details can be made therein withoutdeparting from the spirit and scope of the invention.

All references, issued patents and patent applications cited within thebody of the instant specification are hereby incorporated by referencein their entirety, for all purposes.

TABLE 1 Predicted Fragment EAAcom- SEQID DBID Leader Indices plete EAABCAA A R N D C Q E G H I L K SEQID-00001 P01012 — — 1 0.47 0.22 0.060.05 0.05 0.04 0.01 0.04 0.10 0.03 0.02 0.07 0.08 0.06 SEQID-00002P04405 — — 1 0.36 0.18 0.04 0.08 0.08 0.04 0.02 0.12 0.09 0.04 0.01 0.050.08 0.04 SEQID-00003 P02754 — — 1 0.50 0.16 0.07 0.02 0.03 0.06 0.040.06 0.10 0.01 0.01 0.06 0.15 0.10 SEQID-00004 P02662 — — 1 0.44 0.210.03 0.04 0.04 0.03 0.00 0.07 0.13 0.02 0.03 0.06 0.10 0.08 SEQID-00005P02666 — — 1 0.48 0.25 0.03 0.02 0.02 0.02 0.00 0.10 0.10 0.01 0.03 0.050.12 0.06 SEQID-00006 P00711 — — 1 0.53 0.23 0.02 0.01 0.06 0.09 0.050.06 0.06 0.02 0.03 0.06 0.12 0.09 SEQID-00007 P56552 — — 0 0.28 0.100.02 0.05 0.07 0.09 0.13 0.08 0.08 0.01 0.02 0.02 0.05 0.14 SEQID-00008P29290 — — 0 0.45 0.21 0.03 0.05 0.03 0.11 0.00 0.02 0.21 0.04 0.00 0.070.10 0.06 SEQID-00009 Q5ZMN0 — — 0 0.34 0.20 0.01 0.05 0.06 0.17 0.010.01 0.23 0.03 0.01 0.03 0.14 0.06 SEQID-00010 P04698 — — 0 0.41 0.290.10 0.02 0.05 0.00 0.00 0.22 0.01 0.00 0.01 0.05 0.19 0.00 SEQID-00011P42212 — — 1 0.50 0.20 0.02 0.03 0.05 0.08 0.01 0.04 0.08 0.05 0.05 0.050.09 0.09 SEQID-00012 P56552 — — 0 0.28 0.10 0.02 0.05 0.07 0.09 0.130.08 0.08 0.01 0.02 0.02 0.05 0.14 SEQID-00013 P56552 —  5:54 0 0.280.11 0.02 0.05 0.08 0.08 0.12 0.06 0.09 0.01 0.02 0.02 0.06 0.13SEQID-00014 P56552 —  1:51 0 0.30 0.11 0.02 0.05 0.07 0.09 0.12 0.080.06 0.01 0.02 0.02 0.06 0.15 SEQID-00015 P56552 —  5:51 0 0.30 0.120.03 0.06 0.08 0.08 0.11 0.07 0.07 0.01 0.02 0.02 0.06 0.14 SEQID-00016— — — 0 0.45 0.25 0.08 0.00 0.03 0.07 0.04 0.06 0.14 0.02 0.00 0.05 0.180.07 SEQID-00017 — — — 1 0.45 0.20 0.06 0.01 0.05 0.07 0.02 0.03 0.120.03 0.02 0.08 0.08 0.04 SEQID-00018 P10568 — 693:792 1 0.52 0.19 0.040.17 0.03 0.00 0.01 0.08 0.00 0.02 0.02 0.06 0.11 0.13 SEQID-00019 — — —0 0.48 0.21 0.07 0.31 0.00 0.00 0.00 0.13 0.00 0.02 0.04 0.04 0.11 0.13SEQID-00020 — — — 0 0.52 0.20 0.07 0.09 0.03 0.03 0.03 0.06 0.03 0.020.02 0.07 0.08 0.13 SEQID-00021 — — — 0 0.39 0.23 0.05 0.12 0.08 0.030.02 0.05 0.02 0.02 0.01 0.06 0.10 0.10 SEQID-00022 P04700 — — 0 0.420.29 0.10 0.01 0.05 0.00 0.00 0.22 0.00 0.01 0.01 0.04 0.20 0.00SEQID-00023 P04705 —  40:139 0 0.41 0.36 0.08 0.04 0.05 0.00 0.01 0.230.01 0.01 0.02 0.06 0.26 0.00 SEQID-00024 P15989 — 388:487 0 0.52 0.360.07 0.07 0.04 0.06 0.00 0.07 0.06 0.03 0.00 0.12 0.15 0.04 SEQID-00025P15989 — 341:442 0 0.48 0.36 0.08 0.06 0.04 0.05 0.00 0.06 0.11 0.030.00 0.13 0.16 0.02 SEQID-00026 — — — 0 0.74 0.59 0.06 0.05 0.00 0.000.00 0.00 0.09 0.06 0.00 0.04 0.52 0.00 SEQID-00027 — — — 0 0.51 0.360.01 0.03 0.04 0.02 0.01 0.05 0.11 0.02 0.01 0.07 0.20 0.05 SEQID-00028— — — 0 0.50 0.41 0.03 0.00 0.01 0.09 0.01 0.02 0.20 0.02 0.02 0.09 0.160.00 SEQID-00029 — — — 0 0.37 0.27 0.02 0.08 0.03 0.07 0.00 0.07 0.150.02 0.00 0.05 0.16 0.03 SEQID-00030 P10587 — 1287:1386 0 0.49 0.26 0.020.04 0.06 0.06 0.00 0.12 0.15 0.00 0.02 0.04 0.17 0.13 SEQID-00031Q27991 — 1353:1452 0 0.46 0.23 0.04 0.07 0.02 0.10 0.00 0.11 0.16 0.000.01 0.02 0.17 0.17 SEQID-00032 P29616 —  51:151 0 0.48 0.23 0.04 0.040.04 0.09 0.02 0.04 0.22 0.00 0.01 0.04 0.15 0.15 SEQID-00033 — — — 00.64 0.33 0.04 0.03 0.01 0.05 0.00 0.03 0.13 0.01 0.02 0.06 0.21 0.18SEQID-00034 — — — 0 0.53 0.27 0.08 0.01 0.01 0.05 0.03 0.07 0.09 0.030.00 0.07 0.16 0.14 SEQID-00035 P47807 — 887:986 0 0.57 0.33 0.07 0.060.02 0.05 0.01 0.05 0.05 0.03 0.04 0.02 0.21 0.11 SEQID-00036 — — — 10.64 0.28 0.02 0.01 0.03 0.05 0.03 0.04 0.04 0.03 0.04 0.06 0.17 0.11SEQID-00037 — — — 1 1.00 0.49 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.000.04 0.12 0.28 0.19 SEQID-00038 Q90584 — 424:529 1 0.55 0.28 0.02 0.050.06 0.03 0.03 0.01 0.10 0.03 0.02 0.03 0.19 0.03 SEQID-00039 Q02440 —1443:1545 1 0.54 0.25 0.02 0.05 0.05 0.07 0.03 0.04 0.06 0.02 0.02 0.050.14 0.14 SEQID-00040 P15989 — 399:498 0 0.51 0.34 0.06 0.08 0.04 0.060.00 0.05 0.07 0.03 0.00 0.10 0.13 0.03 SEQID-00041 P10568 — 680:779 10.48 0.18 0.04 0.18 0.03 0.00 0.01 0.08 0.02 0.02 0.02 0.06 0.10 0.10SEQID-00042 P79114 —  982:1083 0 0.25 0.09 0.05 0.03 0.03 0.13 0.01 0.040.15 0.03 0.04 0.01 0.04 0.01 SEQID-00043 P15989 — 398:447 0 0.57 0.410.03 0.08 0.06 0.04 0.00 0.02 0.09 0.01 0.00 0.12 0.18 0.05 SEQID-00044P15989 — 399:448 0 0.59 0.43 0.06 0.08 0.06 0.04 0.00 0.02 0.09 0.010.00 0.12 0.20 0.05 SEQID-00045 P15989 — 402:454 0 0.56 0.43 0.06 0.080.06 0.06 0.00 0.02 0.09 0.02 0.00 0.14 0.20 0.04 SEQID-00046 P15989 —403:454 0 0.55 0.42 0.06 0.08 0.06 0.06 0.00 0.02 0.09 0.02 0.00 0.140.18 0.05 SEQID-00047 P15989 — 406:455 0 0.58 0.44 0.07 0.06 0.06 0.040.00 0.02 0.10 0.02 0.00 0.13 0.21 0.05 SEQID-00048 P69012 — — 0 0.080.03 0.03 0.76 0.00 0.00 0.00 0.00 0.00 0.01 0.00 0.03 0.00 0.00SEQID-00049 — — — 1 0.52 0.19 0.03 0.04 0.05 0.07 0.01 0.04 0.07 0.050.08 0.04 0.08 0.09 SEQID-00050 P02662 —  1:50 0 0.59 0.31 0.05 0.060.04 0.00 0.02 0.05 0.09 0.02 0.05 0.04 0.18 0.09 SEQID-00051 P02662 — 2:51 0 0.59 0.31 0.05 0.06 0.04 0.00 0.02 0.05 0.09 0.02 0.05 0.04 0.180.11 SEQID-00052 P02662 —  3:52 0 0.59 0.33 0.05 0.06 0.04 0.00 0.020.05 0.09 0.02 0.05 0.04 0.18 0.09 SEQID-00053 P02662 —  4:53 0 0.570.31 0.05 0.06 0.06 0.00 0.02 0.05 0.09 0.02 0.05 0.04 0.16 0.09SEQID-00054 P02662 —  5:54 0 0.55 0.29 0.05 0.06 0.06 0.00 0.02 0.050.11 0.02 0.05 0.04 0.14 0.09 SEQID-00055 P02662 —  6:55 0 0.55 0.290.05 0.06 0.06 0.00 0.02 0.05 0.11 0.02 0.05 0.02 0.16 0.09 SEQID-00056P02662 —  78:127 0 0.41 0.28 0.00 0.05 0.02 0.02 0.00 0.09 0.18 0.010.02 0.08 0.12 0.11 SEQID-00057 P02662 —  79:128 0 0.41 0.28 0.00 0.050.02 0.02 0.00 0.09 0.15 0.01 0.02 0.08 0.12 0.11 SEQID-00058 P02662 — 80:129 0 0.41 0.28 0.00 0.05 0.04 0.02 0.00 0.09 0.15 0.01 0.02 0.080.12 0.11 SEQID-00059 P02662 —  86:135 0 0.41 0.27 0.01 0.08 0.04 0.020.00 0.09 0.15 0.01 0.02 0.06 0.13 0.11 SEQID-00060 — — — 1 0.48 0.190.03 0.03 0.04 0.10 0.01 0.03 0.11 0.05 0.08 0.04 0.08 0.06 SEQID-00061— — — 1 0.55 0.17 0.02 0.11 0.04 0.04 0.01 0.02 0.04 0.05 0.08 0.04 0.080.16 SEQID-00062 P33465 — — 0 0.67 0.49 0.03 0.07 0.04 0.03 0.03 0.020.02 0.02 0.04 0.05 0.32 0.02 SEQID-00063 Q9

8D7 — — 0 0.63 0.48 0.05 0.01 0.02 0.01 0.00 0.01 0.04 0.04 0.01 0.200.19 0.01 SEQID-00064 P48923 — — 1 0.62 0.46 0.04 0.00 0.04 0.02 0.010.01 0.04 0.03 0.01 0.19 0.20 0.02 SEQID-00065 P44110 — — 1 0.68 0.490.05 0.00 0.02 0.01 0.00 0.04 0.02 0.07 0.01 0.16 0.24 0.05 SEQID-00066O67248 — — 0 0.70 0.43 0.02 0.01 0.06 0.02 0.00 0.01 0.03 0.02 0.00 0.100.23 0.08 SEQID-00067 P81327 — — 0 0.68 0.48 0.04 0.00 0.03 0.02 0.010.03 0.02 0.03 0.00 0.21 0.18 0.07 SEQID-00068 — — — 0 0.57 0.43 0.000.04 0.04 0.03 0.00 0.07 0.13 0.00 0.03 0.12 0.21 0.03 SEQID-00069 — — —0 0.56 0.47 0.06 0.04 0.04 0.05 0.00 0.04 0.09 0.03 0.00 0.12 0.23 0.02SEQID-00070 — — — 0 0.50 0.40 0.06 0.06 0.04 0.05 0.00 0.06 0.11 0.030.00 0.12 0.19 0.02 SEQID-00071 — — — 0 0.62 0.46 0.05 0.08 0.06 0.040.00 0.02 0.09 0.01 0.00 0.12 0.20 0.05 SEQID-00072 P09860 — — 0 0.460.18 0.03 0.03 0.03 0.14 0.01 0.03 0.17 0.04 0.00 0.06 0.08 0.09SEQID-00073 P35622 — — 0 0.49 0.20 0.04 0.05 0.02 0.12 0.02 0.02 0.160.03 0.00 0.05 0.10 0.13 SEQID-00074 P02586 — — 0 0.42 0.16 0.05 0.060.02 0.12 0.01 0.04 0.19 0.04 0.01 0.06 0.06 0.06 SEQID-00075 P63317 — —0 0.46 0.18 0.03 0.03 0.03 0.14 0.01 0.03 0.17 0.04 0.00 0.06 0.08 0.09SEQID-00076 P63315 — — 0 0.46 0.18 0.0

0.0

0.03 0.14 0.01 0.03 0.17 0.04 0.00 0.06 0.08 0.09 SEQID-00077 D7F1Q2 — —0 0.47 0.21 0.04 0.03 0.02 0.14 0.00 0.03 0.18 0.03 0.00 0.08 0.09 0.07SEQID-00078 Q7ZZ89 — — 0 0.46 0.17 0.0

0.02 0.04 0.14 0.02 0.04 0.16 0.03 0.00 0.06 0.07 0.10 SEQID-00079Q9FF58 — — 0 0.58 0.38 0.01 0.13 0.00 0.02 0.0

0.02 0.02 0.03 0.00 0.07 0.24 0.04 SEQID-00080 P93280 — — 1 0.62 0.330.01 0.03 0.02 0.02 0.03 0.04 0.04 0.03 0.02 0.08 0.21 0.02 SEQID-00081Q67E55 — — 1 0.55 0.30 0.04 0.0

0.02 0.03 0.0

0.05 0.02 0.01 0.04 0.06 0.19 0.02 SEQID-00082 Q35Z72 — — 1 0.48 0.300.07 0.11 0.03 0.04 0.03 0.03 0.04 0.04 0.03 0.03 0.20 0.02 SEQID-00083P14622 — — 1 0.51 0.26 0.09 0.12 0.01 0.01 0.09 0.03 0.05 0.04 0.04 0.040.18 0.05 SEQID-00084 P33626 —  1:61 1 0.32 0.15 0.04 0.02 0.02 0.120.05 0.0

0.16 0.10 0.04 0.10 0.03 0.02 SEQID-00085 P60660 — — 0 0.47 0.20 0.030.05 0.05 0.07 0.02 0.05 0.13 0.05 0.03 0.03 0.09 0.07 SEQID-00086P02607 — — 0 0.46 0.18 0.09 0.05 0.05 0.06 0.02 0.06 0.14 0.05 0.02 0.030.09 0.08 SEQID-00087 P02605 — — 0 0.48 0.19 0.05 0.04 0.08 0.06 0.010.04 0.15 0.04 0.02 0.05 0.08 0.08 SEQID-00088 Q9FRT9 —  1:90 1 0.320.11 0.05 0.02 0.06 0.09 0.11 0.03 0.04 0.05 0.01 0.02 0.07 0.04SEQID-00089 Q95M18 — — 1 0.46 0.19 0.04 0.06 0.03 0.08 0.01 0.03 0.150.02 0.01 0.05 0.08 0.11 SEQID-00090 Q41784 — — 1 0.43 0.17 0.04 0.070.05 0.06 0.02 0.05 0.10 0.04 0.03 0.04 0.08 0.04 SEQID-00091 P09643 — 1:

22 1 0.44 0.20 0.06 0.06 0.04 0.06 0.03 0.04 0.09 0.03 0.03 0.06 0.080.04 SEQID-00092 P02587 — — 0 0.42 0.16 0.05 0.06 0.02 0.12 0.01 0.040.19 0.04 0.01 0.07 0.05 0.06 SEQID-00093 P10246 — — 0 0.45 0.16 0.050.05 0.03 0.12 0.01 0.04 0.18 0.04 0.01 0.07 0.06 0.07 SEQID-00094P02588 — — 0 0.45 0.16 0.05 0.05 0.03 0.13 0.01 0.03 0.18 0.04 0.01 0.070.06 0.07 SEQID-00095 P04119 — — 1 0.50 0.28 0.05 0.05 0.02 0.08 0.090.06 0.10 0.01 0.02 0.03 0.18 0.07 SEQID-00096 Q9T5R4 — — 1 0.53 0.230.02 0.01 0.05 0.10 0.05 0.06 0.06 0.02 0.03 0.06 0.12 0.09 SEQID-00097Q5KR47 — — 0 0.39 0.18 0.08 0.07 0.02 0.07 0.00 0.06 0.24 0.01 0.01 0.040.12 0.15 SEQID-00098 Q030J7 — — 0 0.50 0.25 0.09 0.00 0.04 0.15 0.000.03 0.20 0.01 0.00 0.07 0.08 0.09 SEQID-00099 Q8DH53 — — 0 0.45 0.280.07 0.00 0.05 0.10 0.00 0.04 0.19 0.01 0.00 0.06 0.10 0.09 SEQID-00100Q5FJ18 — — 0 0.46 0.32 0.0

0.00 0.06 0.15 0.00 0.03 0.16 0.02 0.02 0.11 0.06 0.08 SEQID-00101Q9WZD0 — — 0 0.51 0.29 0.03 0.02 0.00 0.14 0.00 0.01 0.15 0.03 0.00 0.090.10 0.12 SEQID-00102 Q74IP1 — — 0 0.45 0.20 0.04 0.03 0.05 0.16 0.000.04 0.14 0.01 0.01 0.10 0.06 0.07 SEQID-00103 Q84MN0 — — 0 0.45 0.190.09 0.05 0.05 0.11 0.01 0.05 0.16 0.04 0.00 0.05 0.09 0.06 SEQID-00104P41040 — — 0 0.45 0.18 0.05 0.05 0.05 0.12 0.01 0.05 0.15 0.03 0.01 0.050.08 0.08 SEQID-00105 P06787 — — 0 0.44 0.23 0.05 0.03 0.06 0.09 0.000.05 0.14 0.03 0.02 0.06 0.13 0.06 SEQID-00106 P93087 — — 0 0.46 0.170.04 0.05 0.05 0.14 0.01 0.05 0.14 0.03 0.01 0.05 0.07 0.08 SEQID-00107P52193 — — 1 0.42 0.14 0.03 0.03 0.04 0.13 0.01 0.04 0.15 0.03 0.02 0.050.06 0.11 SEQID-00108 Q95P22 — — 1 0.44 0.14 0.05 0.02 0.03 0.14 0.000.03 0.12 0.03 0.03 0.06 0.05 0.14 SEQID-00109 P32018 — 656:709 0 0.420.33 0.05 0.00 0.02 0.10 0.00 0.00 0.20 0.04 0.00 0.04 0.16 0.0

SEQID-00110 Q9HD67 — 472:521 0 0.49 0.29 0.02 0.03 0.04 0.10 0.02 0.020.16 0.03 0.02 0.08 0.20 0.04 SEQID-00111 Q03472 — 140:189 0 0.48 0.260.01 0.00 0.02 0.02 0.05 0.06 0.22 0.01 0.02 0.02 0.21 0.13 SEQID-00112Q02440 — 461:511 1 0.50 0.23 0.01 0.00 0.06 0.07 0.02 0.12 0.12 0.010.02 0.07 0.13 0.06 SEQID-00113 Q13402 — 452:509 1 0.52 0.24 0.039 0.020.08 0.06 0.01 0.07 0.11 0.00 0.06 0.10 0.11 0.04 SEQID-00114 Q90688 —446:495 1 0.51 0.24 0.01 0.05 0.00 0.04 0.02 0.02 0.25 0.03 0.02 0.040.08 0.07 SEQID-00115 Q29092 — 703:803 0 0.32 0.13 0.04 0.05 0.01 0.160.00 0.02 0.27 0.01 0.00 0.02 0.08 0.04 SEQID-00116 Q29092 — 704:803 00.32 0.14 0.04 0.06 0.01 0.16 0.00 0.02 0.26 0.02 0.00 0.02 0.08 0.05SEQID-00117 Q02440 — 413:512 1 0.52 0.22 0.02 0.00 0.08 0.06 0.02 0.090.12 0.01 0.05 0.09 0.09 0.06 SEQID-00118 Q28970 — 427:527 1 0.51 0.210.02 0.04 0.08 0.06 0.01 0.05 0.12 0.01 0.09 0.09 0.10 0.05 SEQID-00119Q90688 — 382:481 1 0.46 0.24 0.05 0.03 0.04 0.05 0.03 0.03 0.17 0.030.02 0.07 0.07 0.07 SEQID-00120 Q90688 — 398:498 1 0.46 0.22 0.04 0.040.03 0.04 0.03 0.03 0.20 0.03 0.02 0.07 0.06 0.07 SEQID-00121 Q28063 — 23:225 0 0.29 0.12 0.09 0.02 0.04 0.08 0.00 0.03 0.21 0.05 0.01 0.040.04 0.04 SEQID-00122 Q28063 —  2:202 0 0.26 0.10 0.04 0.02 0.04 0.090.01 0.05 0.21 0.04 0.01 0.03 0.09 0.04 SEQID-00123 Q95M18 — 118:318 10.46 0.20 0.04 0.02 0.06 0.07 0.00 0.03 0.18 0.03 0.02 0.06 0.08 0.09SEQID-00124 P08110 — 120:321 1 0.48 0.19 0.09 0.02 0.06 0.07 0.00 0.030.18 0.03 0.02 0.05 0.07 0.11 SEQID-00125 P22418 —  75:275 1 0.40 0.270.05 0.03 0.04 0.06 0.09 0.05 0.10 0.05 0.01 0.09 0.08 0.03 SEQID-00126P79114 —  913:1115 1 0.26 0.11 0.04 0.06 0.039 0.11 0.02 0.06 0.15 0.030.02 0.02 0.06 0.02 SEQID-00127 P04119 — — 1 0.50 0.28 0.05 0.05 0.020.0

0.09 0.06 0.10 0.01 0.02 0.03 0.18 0.07 SEQID-00128 P06714 — — 1 0.530.24 0.09 0.10 0.01 0.05 0.01 0.02 0.04 0.03 0.08 0.01 0.17 0.04SEQID-00129 A1AAQ3 — — 1 0.51 0.26 0.06 0.08 0.01 0.05 0.01 0.09 0.060.03 0.06 0.02 0.13 0.02 SEQID-00130 P02114 — — 1 0.56 0.24 0.07 0.060.05 0.05 0.02 0.04 0.05 0.03 0.06 0.05 0.12 0.08 SEQID-00131 P67975 — —1 0.50 0.25 0.06 0.03 0.04 0.05 0.0

0.06 0.11 0.02 0.02 0.06 0.13 0.11 SEQID-00132 Q90584 — 436:486 0 0.600.41 0.04 0.05 0.08 0.02 0.00 0.02 0.07 0.04 0.02 0.04 0.32 0.07SEQID-00133 A6QP

B3 — 473:523 0 0.61 0.35 0.04 0.10 0.02 0.00 0.00 0.00 0.15 0.04 0.000.02 0.30 0.11 SEQID-00134 P22281 —  82:134 0 0.58 0.46 0.04 0.06 0.020.06 0.02 0.00 0.02 0.02 0.02 0.14 0.24 0.0

SEQID-00135 P01958 —  63:114 0 0.61 0.38 0.06 0.03 0.04 0.10 0.02 0.000.00 0.03 0.12 0.00 0.29 0.05 SEQID-00136 Q9T5N7 —  63:114 0 0.62 0.360.09 0.03 0.02 0.06 0.00 0.00 0.02 0.02 0.12 0.00 0.27 0.07 SEQID-00137Q17R14 — 270:321 0 0.64 0.39 0.06 0.03 0.02 0.03 0.00 0.00 0.07 0.030.02 0.10 0.20 0.09 SEQID-00138 P47807 —  952:1003 0 0.59 0.35 0.08 0.030.00 0.06 0.00 0.05 0.05 0.04 0.08 0.04 0.27 0.05 SEQID-00139 Q27991 —1396:1446 0 0.49 0.31 0.02 0.08 0.02 0.11 0.00 0.11 0.11 0.00 0.02 0.020.23 0.13 SEQID-00140 P12106 — 170:120 1 0.70 0.32 0.00 0.00 0.02 0.060.02 0.02 0.04 0.02 0.05 0.10 0.14 0.11 SEQID-00141 P32191 — 112:163 10.58 0.31 0.05 0.05 0.04 0.02 0.02 0.02 0.09 0.02 0.07 0.11 0.15 0.06SEQID-00142 P19524 — 1398:1449 1 0.56 0.25 0.01 0.10 0.06 0.02 0.03 0.080.06 0.03 0.04 0.04 0.18 0.08 SEQID-00143 Q03262 — 225:277 1 0.65 0.300.01 0.00 0.04 0.02 0.02 0.00 0.11 0.03 0.02 0.06 0.13 0.15 SEQID-00144P32492 — 1275:1325 1 0.67 0.25 0.02 0.00 0.09 0.08 0.03 0.02 0.02 0.000.02 0.04 0.15 0.11 SEQID-00145 P12863 —  82:132 1 0.51 0.33 0.05 0.060.04 0.02 0.02 0.02 0.12 0.06 0.03 0.04 0.17 0.05 SEQID-00146 P12106 —159:209 1 0.67 0.29 0.01 0.00 0.02 0.06 0.02 0.04 0.04 0.02 0.05 0.080.14 0.09 SEQID-00147 P32492 — 1092:1193 1 0.57 0.36 0.00 0.04 0.08 0.040.01 0.01 0.08 0.04 0.01 0.07 0.17 0.06 SEQID-00148 A6QR56 — 589:691 00.47 0.34 0.10 0.14 0.02 0.01 0.02 0.05 0.09 0.03 0.02 0.01 0.21 0.03SEQID-00149 P47807 — 888:988 0 0.56 0.32 0.07 0.06 0.02 0.05 0.01 0.060.05 0.03 0.05 0.02 0.21 0.09 SEQID-00150 P32492 — 1218:1319 1 0.67 0.250.02 0.00 0.08 0.08 0.01 0.01 0.06 0.00 0.03 0.06 0.14 0.13 SEQID-00151P79114 — 688:788 1 0.48 0.26 0.05 0.14 0.03 0.03 0.02 0.06 0.09 0.010.02 0.04 0.15 0.10 SEQID-00152 Q5MIB5 — 492:592 1 0.53 0.27 0.01 0.050.07 0.05 0.02 0.05 0.09 0.01 0.02 0.07 0.14 0.13 SEQID-00153 P04119 — 28:129 1 0.51 0.26 0.06 0.01 0.04 0.10 0.02 0.05 0.08 0.02 0.02 0.060.17 0.10 SEQID-00154 P06642 —  14:115 1 0.55 0.27 0.03 0.05 0.07 0.060.02 0.01 0.06 0.04 0.04 0.05 0.14 0.08 SEQID-00155 Q2XQV4 — 108:213 10.49 0.26 0.05 0.06 0.04 0.08 0.02 0.02 0.03 0.04 0.02 0.05 0.15 0.06SEQID-00156 Q02440 — 1448:1548 1 0.52 0.25 0.02 0.07 0.05 0.06 0.03 0.040.07 0.03 0.02 0.05 0.15 0.12 SEQID-00157 Q49068 — — 1 0.45 0.23 0.040.03 0.06 0.06 0.01 0.06 0.07 0.03 0.03 0.06 0.10 0.05 SEQID-00158P32492 — 1086:1287 1 0.58 0.29 0.02 0.03 0.07 0.06 0.00 0.02 0.08 0.020.02 0.05 0.15 0.10 SEQID-00159 Q76F

2 —  59:260 1 0.46 0.23 0.03 0.0

0.06 0.07 0.03 0.03 0.06 0.05 0.03 0.04 0.12 0.03 SEQID-00160 P32492 —1115:1316 1 0.61 0.28 0.02 0.01 0.07 0.06 0.00 0.02 0.07 0.02 0.02 0.050.14 0.11 SEQID-00161 Q41874 — 113:313 1 0.49 0.27 0.04 0.09 0.07 0.040.01 0.06 0.04 0.01 0.02 0.05 0.12 0.05 SEQID-00162 P52768 — — 0 0.640.53 0.01 0.00 0.08 0.02 0.00 0.02 0.02 0.01 0.02 0.14 0.34 0.02SEQID-00163 P8

479 — — 1 0.72 0.43 0.02 0.01 0.02 0.02 0.00 0.02 0.03 0.01 0.05 0.130.26 0.07 SEQID-00164 Q31K24 — — 0 0.67 0.51 0.04 0.05 0.05 0.02 0.000.04 0.00 0.04 0.00 0.05 0.24 0.00 SEQID-00165 P51316 — — 0 0.69 0.520.03 0.00 0.02 0.00 0.00 0.06 0.02 0.05 0.00 0.12 0.23 0.02 SEQID-00166Q36967 —  1:105 0 0.65 0.46 0.08 0.04 0.02 0.00 0.00 0.03 0.03 0.02 0.020.12 0.26 0.00 SEQID-00167 O21402 — — 1 0.65 0.39 0.05 0.03 0.05 0.000.00 0.05 0.02 0.02 0.02 0.06 0.29 0.02 SEQID-00168 Q47872 — — 1 0.680.41 0.04 0.02 0.05 0.00 0.00 0.05 0.02 0.02 0.03 0.10 0.27 0.02SEQID-00169 Q85X26 — — 0 0.60 0.43 0.01 0.00 0.11 0.02 0.00 0.02 0.020.01 0.02 0.13 0.25 0.00 SEQID-00170 P14092 — — 1 0.63 0.39 0.05 0.030.05 0.00 0.00 0.04 0.02 0.02 0.02 0.09 0.28 0.02 SEQID-00171 Q36964 — 1:219 1 0.65 0.40 0.06 0.04 0.04 0.00 0.00 0.04 0.02 0.03 0.02 0.090.25 0.01 SEQID-00172 Q70RQ2 — — 0 0.64 0.39 0.07 0.01 0.06 0.01 0.030.02 0.02 0.02 0.04 0.07 0.24 0.00 SEQID-00173 P48178 — — 1 0.64 0.370.05 0.04 0.04 0.00 0.00 0.05 0.02 0.03 0.02 0.09 0.23 0.01 SEQID-00174Q36090 —  1:133 1 0.65 0.34 0.02 0.05 0.05 0.00 0.00 0.03 0.03 0.03 0.030.07 0.23 0.01 SEQID-00175 Q31721 —  1:58 0 0.63 0.38 0.07 0.00 0.050.02 0.03 0.02 0.04 0.04 0.02 0.14 0.19 0.00 SEQID-00176 Q38LTZ5 — — 10.67 0.35 0.05 0.03 0.05 0.00 0.00 0.05 0.02 0.03 0.03 0.10 0.20 0.02SEQID-00177 A4GYW9 —  13:120 1 0.66 0.41 0.04 0.00 0.07 0.01 0.02 0.010.01 0.05 0.01 0.11 0.21 0.01 SEQID-00178 Q31720 — 150:252 1 0.64 0.370.06 0.03 0.02 0.00 0.03 0.01 0.03 0.04 0.02 0.10 0.22 0.01 SEQID-00179P27572 —  6:106 1 0.61 0.40 0.01 0.04 0.02 0.03 0.04 0.02 0.03 0.02 0.010.15 0.21 0.01 SEQID-00180 P11631 — 360:460 1 0.67 0.35 0.03 0.03 0.030.00 0.01 0.01 0.04 0.02 0.05 0.11 0.23 0.01 SEQID-00181 Q00506 — 30:130 1 0.68 0.36 0.03 0.01 0.02 0.02 0.01 0.03 0.03 0.00 0.01 0.070.28 0.03 SEQID-00182 P92487 — 272:373 1 0.63 0.38 0.04 0.04 0.01 0.010.01 0.04 0.02 0.02 0.02 0.13 0.21 0.02 SEQID-00183 B2XWJ4 —  62:163 10.63 0.38 0.01 0.01 0.07 0.04 0.01 0.06 0.03 0.04 0.01 0.18 0.17 0.02SEQID-00184 P27572 —  50:150 1 0.65 0.33 0.02 0.03 0.01 0.03 0.03 0.020.05 0.02 0.01 0.10 0.17 0.02 SEQID-00185 P27572 —  22:122 1 0.62 0.370.01 0.05 0.02 0.02 0.02 0.02 0.03 0.03 0.01 0.16 0.17 0.02 SEQID-00186P27572 — 130:236 1 0.68 0.35 0.04 0.05 0.00 0.02 0.01 0.05 0.03 0.020.01 0.11 0.17 0.03 SEQID-00187 Q31720 —  43:144 1 0.69 0.35 0.01 0.000.05 0.01 0.02 0.04 0.02 0.04 0.02 0.10 0.18 0.04 SEQID-00188 O47872 —105:206 0 0.70 0.48 0.04 0.04 0.02 0.00 0.00 0.02 0.03 0.02 0.02 0.120.32 0.00 SEQID-00189 P50681 —  14:114 1 0.69 0.37 0.02 0.04 0.05 0.000.00 0.03 0.00 0.02 0.01 0.06 0.30 0.03 SEQID-00190 P14092 —  69:170 00.63 0.39 0.06 0.04 0.04 0.00 0.00 0.02 0.02 0.03 0.03 0.06 0.32 0.00SEQID-00191 O47872 —  54:154 1 0.68 0.43 0.03 0.03 0.03 0.00 0.00 0.030.02 0.02 0.04 0.14 0.27 0.02 SEQID-00192 P50681 — 111:212 0 0.64 0.450.08 0.04 0.02 0.00 0.00 0.04 0.04 0.02 0.03 0.14 0.29 0.00 SEQID-00193Q5ZMN0 — 44:93 0 0.53 0.36 0.01 0.08 0.12 0.02 0.00 0.00 0.09 0.02 0.020.06 0.26 0.07 SEQID-00194 Q5ZMN0 — 46:95 0 0.54 0.36 0.01 0.0

0.14 0.02 0.00 0.00 0.07 0.02 0.02 0.06 0.26 0.07 SEQID-00195 Q5ZMN0 —47:96 0 0.52 0.36 0.01 0.08 0.14 0.02 0.00 0.00 0.07 0.02 0.02 0.06 0.260.07 SEQID-00196 Q5ZMN0 —  1:146 0 0.53 0.30 0.00 0.07 0.10 0.06 0.010.01 0.09 0.02 0.02 0.05 0.21 0.10 SEQID-00197 Q5ZMN0 —  1:147 0 0.520.30 0.00 0.07 0.10 0.06 0.01 0.01 0.09 0.02 0.02 0.05 0.21 0.10SEQID-00198 Q5ZMN0 —  1:148 0 0.53 0.30 0.00 0.06 0.10 0.05 0.01 0.010.09 0.02 0.02 0.05 0.21 0.10 SEQID-00199 Q5ZMN0 —  1:149 0 0.52 0.290.00 0.06 0.10 0.06 0.01 0.01 0.09 0.02 0.02 0.05 0.21 0.10 SEQID-00200Q5ZMN0 —  1:150 0 0.52 0.29 0.01 0.06 0.10 0.06 0.01 0.01 0.09 0.02 0.020.05 0.21 0.10 SEQID-00201 Q5ZMN0 —  1:151 0 0.52 0.29 0.01 0.06 0.100.07 0.01 0.01 0.09 0.02 0.02 0.05 0.20 0.10 SEQID-00202 Q5ZMN0 —  1:1520 0.51 0.29 0.01 0.06 0.10 0.07 0.01 0.01 0.10 0.02 0.02 0.05 0.20 0.10SEQID-00203 Q5ZMN0 —  1:153 0 0.51 0.29 0.01 0.06 0.10 0.07 0.01 0.010.10 0.02 0.02 0.05 0.20 0.10 SEQID-00204 Q5ZMN0 —  1:154 0 0.51 0.280.01 0.06 0.10 0.07 0.01 0.01 0.10 0.02 0.02 0.05 0.20 0.09 SEQID-00205Q5ZMN0 —  1:161 0 0.49 0.27 0.01 0.06 0.09 0.08 0.01 0.01 0.11 0.02 0.020.04 0.19 0.09 SEQID-00206 P35580 — 117:166 0 0.56 0.24 0.03 0.10 0.020.02 0.02 0.10 0.10 0.00 0.02 0.00 0.16 0.14 SEQID-00207 Q9JLT0 —127:193 1 0.54 0.22 0.01 0.07 0.01 0.01 0.00 0.11 0.20 0.01 0.03 0.010.15 0.15 SEQID-00208 Q61879 — 152:206 0 0.43 0.20 0.04 0.02 0.02 0.020.00 0.12 0.33 0.01 0.02 0.02 0.16 0.14 SEQID-00209 Q27991 — 102:206 10.49 0.21 0.06 0.07 0.02 0.01 0.01 0.13 0.17 0.00 0.02 0.01 0.15 0.14SEQID-00210 Q9JLT0 — 127:226 1 0.49 0.21 0.05 0.03 0.01 0.01 0.00 0.110.23 0.00 0.03 0.02 0.15 0.13 SEQID-00211 Q9JLT0 — 127:231 1 0.48 0.210.04 0.09 0.01 0.02 0.00 0.10 0.23 0.00 0.03 0.02 0.15 0.12 SEQID-00212Q27991 — 141:190 0 0.51 0.28 0.04 0.05 0.00 0.12 0.00 0.09 0.15 0.000.02 0.00 0.23 0.17 SEQID-00213 Q27991 — 136:185 0 0.51 0.28 0.04 0.050.02 0.0

0.00 0.07 0.18 0.01 0.00 0.02 0.21 0.18 SEQID-00214 Q27991 — 116:185 00.51 0.27 0.04 0.04 0.01 0.11 0.00 0.11 0.13 0.01 0.00 0.01 0.21 0.17SEQID-00215 Q27991 — 146:200 0 0.51 0.29 0.02 0.07 0.02 0.11 0.00 0.100.12 0.00 0.02 0.02 0.21 0.18 SEQID-00216 Q27991 — 146:210 0 0.52 0.270.03 0.06 0.01 0.10 0.00 0.12 0.12 0.00 0.02 0.01 0.20 0.18 SEQID-00217Q27991 — 131:185 0 0.50 0.29 0.03 0.05 0.02 0.13 0.00 0.06 0.16 0.010.00 0.02 0.21 0.16 SEQID-00218 Q27991 — 136:190 0 0.50 0.27 0.03 0.050.02 0.11 0.00 0.0

0.16 0.01 0.02 0.02 0.21 0.16 SEQID-00219 Q27991 — 146:195 0 0.50 0.300.02 0.0

0.00 0.12 0.00 0.11 0.11 0.00 0.02 0.02 0.21 0.15 SEQID-00220 Q27991 —126:190 0 0.52 0.26 0.03 0.04 0.02 0.15 0.00 0.07 0.14 0.01 0.02 0.010.19 0.19 SEQID-00221 Q27991 — 141:200 0 0.51 0.28 0.0

0.07 0.02 0.10 0.00 0.09 0.15 0.00 0.02 0.02 0.21 0.18 SEQID-00222Q27991 — 31:80 0 0.41 0.20 0.06 0.03 0.06 0.06 0.00 0.11 0.21 0.02 0.000.02 0.16 0.14 SEQID-00223 Q27991 — 161:210 0 0.50 0.24 0.04 0.05 0.020.12 0.00 0.13 0.11 0.00 0.02 0.02 0.19 0.17 SEQID-00224 Q27991 —126:185 0 0.53 0.27 0.0

0.04 0.02 0.13 0.00 0.06 0.15 0.01 0.00 0.02 0.19 0.20 SEQID-00225Q27991 — 111:210 0 0.50 0.26 0.04 0.05 0.02 0.11 0.00 0.12 0.12 0.000.01 0.02 0.19 0.18 SEQID-00226 Q27991 — 116:215 0 0.50 0.26 0.04 0.040.0

0.11 0.00 0.12 0.12 0.00 0.01 0.03 0.18 0.18 SEQID-00227 Q27991 —126:225 0 0.46 0.22 0.04 0.03 0.0

0.12 0.00 0.03 0.14 0.00 0.01 0.03 0.15 0.17 SEQID-00228 Q27991 —126:237 0 0.45 0.21 0.0

0.03 0.0

0.11 0.00 0.07 0.17 0.00 0.01 0.03 0.15 0.18 SEQID-00229 Q9JLT0 —124:174 0 0.40 0.22 0.04 0.13 0.06 0.05 0.00 0.05 0.21 0.01 0.00 0.020.19 0.06 SEQID-00230 Q9JLT0 — 194:244 0 0.45 0.20 0.11 0.03 0.04 0.000.00 0.11 0.21 0.02 0.00 0.04 0.14 0.20 SEQID-00231 Q27991 — 139:227 00.41 0.20 0.08 0.0

0.06 0.03 0.00 0.11 0.18 0.01 0.00 0.03 0.15 0.11 SEQID-00232 Q61879 —154:252 0 0.41 0.19 0.09 0.11 0.05 0.03 0.00 0.10 0.16 0.01 0.00 0.020.14 0.15 SEQID-00233 P15989 —  99:308 0 0.52 0.37 0.07 0.05 0.04 0.070.00 0.04 0.08 0.04 0.00 0.13 0.17 0.03 SEQID-00234 P15989 —  99:203 00.51 0.37 0.07 0.06 0.04 0.07 0.00 0.05 0.08 0.04 0.00 0.13 0.16 0.03SEQID-00235 P15989 —  49:166 0 0.44 0.28 0.10 0.06 0.04 0.06 0.00 0.050.09 0.05 0.00 0.07 0.15 0.04 SEQID-00236 Q90339 — 201:265 0 0.45 0.210.06 0.06 0.02 0.11 0.00 0.12 0.16 0.02 0.02 0.00 0.18 0.15 SEQID-00237Q

E41 — 216:265 0 0.48 0.21 0.04 0.08 0.02 0.10 0.00 0.07 0.18 0.02 0.000.00 0.18 0.20 SEQID-00238 Q8MJV0 — 146:200 0 0.56 0.21 0.05 0.00 0.040.09 0.02 0.00 0.23 0.01 0.02 0.04 0.14 0.22 SEQID-00239 Q9

V62 — 241:290 0 0.48 0.17 0.02 0.08 0.02 0.09 0.00 0.08

0.19 0.01 0.00 0.02 0.15 0.21 SEQID-00240 Q5

X39 — 236:285 0 0.45 0.19 0.02 0.08 0.02 0.12 0.00 0.09 0.17 0.02 0.000.02 0.17 0.20 SEQID-00241 Q9

V61 — 151:265 0 0.52 0.21 0.0

0.04 0.0

0.10 0.00 0.07 0.18 0.01 0.02 0.02 0.16 0.19 SEQID-00242 Q79102 — 55:104 0 0.75 0.53 0.0

0.03 0.00 0.02 0.00 0.04 0.02 0.01 0.00 0.0

0.42 0.00 SEQID-00243 Q

ZBI9 — 192:241 0 0.66 0.47 0.04 0.03 0.00 0.00 0.02 0.05 0.02 0.04 0.000.02 0.43 0.00 SEQID-00244 P18937 — 119:170 0 0.71 0.46 0.0

0.00 0.02 0.00 0.00 0.05 0.00 0.04 0.00 0.08 0.37 0.02 SEQID-00245P18937 — 106:157 1 0.73 0.43 0.01 0.00 0.02 0.00 0.00 0.04 0.02 0.020.02 0.04 0.36 0.02 SEQID-00246 Q90592 — 200:250 0 0.69 0.51 0.04 0.000.02 0.04 0.00 0.07 0.02 0.0

0.03 0.0

0.39 0.00 SEQID-00247 Q90592 — 152:250 1 0.61 0.43 0.06 0.03 0.01 0.020.01 0.04 0.03 0.07 0.03 0.0

0.30 0.01 SEQID-00248 O478

—  56:109 0 0.69 0.43 0.09 0.00 0.02 0.02 0.00 0.00 0.02 0.01 0.00 0.040.39 0.04 SEQID-00249 O478

—  11:109 1 0.65 0.40 0.07 0.03 0.02 0.02 0.00 0.02 0.02 0.03 0.01 0.070.31 0.05 SEQID-00250 A1L504 —  57:107 0 0.65 0.44 0.05 0.03 0.00 0.020.00 0.05 0.07 0.04 0.05 0.00 0.40 0.00 SEQID-00251 A1L504 — 260:327 10.63 0.37 0.06 0.06 0.05 0.03 0.00 0.02 0.02 0.02 0.02 0.03 0.30 0.05SEQID-00252 Q

2LM8 — 203:253 0 0.63 0.44 0.04 0.11 0.00 0.06 0.00 0.07 0.00 0.03 0.070.00 0.39 0.02 SEQID-00253 Q767L9 — 139:230 1 0.66 0.44 0.0

0.06 0.00 0.02 0.02 0.01 0.04 0.0

0.05 0.03 0.31 0.02 SEQID-00254 Q32LM8 — 150:230 1 0.63 0.43 0.03 0.070.00 0.0

0.01 0.01 0.04 0.03 0.04 0.02 0.32 0.03 SEQID-00255 Q6F4F5 —  

:55 0 0.70 0.45 0.0

0.0

0.02 0.00 0.00 0.00 0.02 0.0

0.0

0.02 0.38 0.05 SEQID-00256 Q6F4F5 —  1:52 1 0.70 0.46 0.05 0.03 0.020.00 0.00 0.00 0.05 0.05 0.02 0.02 0.37 0.05 SEQID-00257 Q35920 — 58:111 1 0.73 0.41 0.02 0.00 0.06 0.00 0.00 0.02 0.00 0.04 0.02 0.020.36 0.02 SEQID-00258 P49208 —  1:50 1 0.69 0.39 0.00 0.18 0.02 0.000.00 0.02 0.00 0.01 0.05 0.02 0.34 0.08 SEQID-00259 P00729 —  2:52 00.60 0.35 0.07 0.03 0.00 0.11 0.02 0.05 0.02 0.04 0.03 0.02 0.31 0.12SEQID-00260 Q58

T4 — 337:386 0 0.69 0.43 0.03 0.0

0.02 0.04 0.04 0.00 0.02 0.05 0.03 0.02 0.34 0.05 SEQID-00261 Q066

9 — 422:473 0 0.64 0.43 0.00 0.0

0.10 0.04 0.02 0.02 0.04 0.01 0.02 0.06 0.34 0.02 SEQID-00262 Q9UKT8 —15:69 0 0.61 0.37 0.01 0.05 0.05 0.05 0.00 0.04 0.06 0.01 0.04 0.02 0.320.06 SEQID-00263 A1

P6 — 17:68 0 0.64 0.41 0.02 0.00 0.00 0.02 0.03 0.04 0.00 0.02 0.02 0.020.34 0.02 SEQID-00264 Q9

V61 — 102:344 0 0.44 0.19 0.06 0.06 0.02 0.0

0.01 0.0

0.21 0.01 0.01 0.04 0.12 0.17 SEQID-00265 Q27991 —  20:289 0 0.38 0.200.06 0.10 0.03 0.07 0.00 0.09 0.20 0.01 0.01 0.02 0.15 0.13 SEQID-00266— — — 0 0.52 0.26 0.03 0.04 0.01 0.15 0.00 0.07 0.14 0.01 0.02 0.01 0.220.18 SEQID-00267 — — — 0 0.52 0.26 0.03 0.04 0.01 0.15 0.00 0.07 0.140.01 0.02 0.00 0.25 0.18 SEQID-00268 — — — 0 0.52 0.28 0.03 0.04 0.010.15 0.00 0.07 0.14 0.01 0.02 0.00 0.28 0.17 SEQID-00269 — — — 0 0.530.31 0.02 0.04 0.01 0.15 0.00 0.07 0.13 0.01 0.02 0.00 0.31 0.17SEQID-00270 — — — 0 0.56 0.33 0.00 0.04 0.01 0.15 0.00 0.07 0.13 0.010.02 0.00 0.33 0.16 SEQID-00271 — — — 0 0.57 0.36 0.00 0.04 0.00 0.150.00 0.07 0.13 0.01 0.02 0.00 0.36 0.16 SEQID-00272 — — — 0 0.53 0.280.02 0.04 0.01 0.15 0.00 0.07 0.13 0.01 0.02 0.00 0.28 0.18 SEQID-00273— — — 0 0.56 0.31 0.01 0.04 0.00 0.15 0.00 0.07 0.13 0.01 0.02 0.00 0.310.18 SEQID-00274 — — — 0 0.57 0.33 0.01 0.04 0.00 0.15 0.00 0.07 0.130.00 0.02 0.00 0.33 0.18 SEQID-00275 — — — 0 0.58 0.36 0.00 0.04 0.000.15 0.00 0.07 0.13 0.00 0.02 0.00 0.36 0.1

SEQID-00276 — — — 0 0.60 0.36 0.01 0.04 0.00 0.15 0.00 0.07 0.13 0.000.02 0.00 0.36 0.18 SEQID-00277 Q1WLP9 — 170:263 1 0.67 0.33 0.06 0.020.01 0.00 0.04 0.01 0.05 0.01 0.04 0.08 0.14 0.11 SEQID-00278 A3DBX3 — —1 0.43 0.15 0.02 0.06 0.07 0.07 0.00 0.02 0.05 0.05 0.01 0.04 0.05 0.07SEQID-00279 — — — 0 0.57 0.35 0.00 0.04 0.00 0.15 0.00 0.07 0.13 0.010.02 0.00 0.35 0.16 SEQID-00280 — — — 0 0.57 0.35 0.01 0.04 0.00 0.150.00 0.07 0.13 0.00 0.02 0.00 0.35 0.18 SEQID-00281 P05804 — — 1 0.460.19 0.05 0.07 0.05 0.07 0.01 0.06 0.08 0.04 0.04 0.05 0.07 0.05SEQID-00282 O60167 — 51:75 1 0.75 0.32 0.00 0.05 0.00 0.00 0.03 0.040.08 0.00 0.04 0.07 0.15 0.13 SEQID-00283 Q0WvK7 —  53:105 1 0.57 0.270.01 0.14 0.02 0.05 0.03 0.02 0.06 0.00 0.04 0.07 0.12 0.12 SEQID-00284Q94A52 — 149:261 1 0.54 0.26 0.02 0.10 0.00 0.06 0.02 0.03 0.11 0.020.03 0.06 0.12 0.10 SEQID-00285 Q5F479 — 556:615 1 0.64 0.28 0.03 0.130.00 0.02 0.01 0.02 0.11 0.00 0.06 0.06 0.14 0.11 SEQID-00286 Q08213 —177:230 1 0.65 0.31 0.00 0.05 0.04 0.04 0.03 0.04 0.06 0.02 0.04 0.070.14 0.12 SEQID-00287 P38111 — 1093:1165 1 0.59 0.

0 0.02 0.04 0.05 0.10 0.04 0.02 0.06 0.01 0.03 0.08 0.13 0.11SEQID-00288 O93262 — — 1 0.55 0.27 0.02 0.06 0.02 0.06 0.03 0.06 0.070.01 0.03 0.06 0.13 0.09 SEQID-00289 O64837 — — 1 0.61 0.26 0.02 0.060.02 0.03 0.01 0.01 0.10 0.0

0.03 0.06 0.12 0.09 SEQID-00290 Q54K39 — — 1 0.53 0.28 0.03 0.05 0.030.04 0.01 0.02 0.09 0.05 0.03 0.09 0.11 0.09 SEQID-00291 P38111 —1093:1182 1 0.57 0.27 0.03 0.03 0.06 0.08 0.03 0.04 0.06 0.01 0.03 0.070.13 0.10 SEQID-00292 P38111 — 1093:1162 1 0.57 0.27 0.02 0.04 0.06 0.100.04 0.02 0.06 0.01 0.03 0.07 0.13 0.11 SEQID-00293 P38111 — 1092:1166 10.59 0.29 0.02 0.04 0.05 0.09 0.04 0.01 0.06 0.01 0.03 0.0

0.13 0.10 SEQID-00294 P33111 — 1093:1168 1 0.58 0.29 0.02 0.04 0.05 0.090.04 0.01 0.06 0.01 0.03 0.08 0.13 0.10 SEQID-00295 P38111 — 1091:1164 10.59 0.30 0.02 0.04 0.05 0.09 0.04 0.02 0.06 0.01 0.03 0.09 0.13 0.11SEQID-00296 P38111 — 1089:1164 1 0.58 0.29 0.02 0.04 0.05 0.11 0.04 0.010.06 0.01 0.03 0.09 0.13 0.10 SEQID-00297 P02190 — — 1 0.58 0.20 0.070.02 0.03 0.05 0.00 0.04 0.10 0.05 0.10 0.04 0.11 0.14 SEQID-00298P02192 — — 1 0.59 0.20 0.07 0.02 0.03 0.05 0.00 0.0

0.10 0.04 0.10 0.04 0.11 0.14 SEQID-00299 P02189 — — 1 0.56 0.21 0.060.02 0.02 0.05 0.00 0.05 0.11 0.05 0.07 0.04 0.12 0.14 SEQID-00300F1RJW7 — — 1 0.45 0.21 0.04 0.03 0.03 0.14 0.00 0.02 0.15 0.02 0.02 0.050.10 0.07 SEQID-00301 Q05JF3 — — 1 0.44 0.21 0.05 0.03 0.04 0.12 0.000.02 0.16 0.02 0.02 0.04 0.10 0.07 SEQID-00302 406710553 — — 1 0.49 0.260.08 0.04 0.02 0.07 0.01 0.04 0.09 0.05 0.02 0.05 0.12 0.09 SEQID-00303406715845 — — 1 0.46 0.23 0.05 0.07 0.03 0.07 0.01 0.05 0.08 0.04 0.020.09 0.08 0.06 SEQID-00304 406711970 — — 1 0.44 0.23 0.02 0.09 0.03 0.090.01 0.04 0.08 0.04 0.04 0.07 0.09 0.06 SEQID-00305 A6QLL8 — — 1 0.440.21 0.08 0.06 0.04 0.04 0.02 0.05 0.08 0.04 0.03 0.06 0.10 0.09SEQID-00306 B7TJ13 — — 1 0.52 0.23 0.06 0.04 0.05 0.06 0.02 0.02 0.070.05 0.02 0.05 0.10 0.12 SEQID-00307 P39824 — — 1 0.51 0.22 0.07 0.060.06 0.07 0.01 0.02 0.05 0.03 0.02 0.08 0.09 0.11 SEQID-00308 P25152 — —1 0.48 0.21 0.07 0.04 0.04 0.05 0.00 0.04 0.09 0.04 0.03 0.06 0.09 0.11SEQID-00309 O32150 — — 1 0.40 0.16 0.05 0.07 0.07 0.09 0.00 0.02 0.070.04 0.04 0.03 0.08 0.06 SEQID-00310 Q9K6A3 — — 1 0.39 0.14 0.05 0.140.04 0.05 0.03 0.05 0.09 0.05 0.02 0.03 0.06 0.02 SEQID-00311 P42249 — —1 0.38 0.14 0.07 0.15 0.05 0.06 0.06 0.06 0.06 0.06 0.02 0.06 0.06 0.06SEQID-00312

— — 1 0.47 0.23 0.03 0.05 0.04 0.04 0.00 0.06 0.13 0.04 0.04 0.06 0.100.05 SEQID-00313 P39844 — — 1 0.49 0.23 0.05 0.04 0.04 0.07 0.00 0.060.07 0.05 0.02 0.05 0.11 0.10 SEQID-00314 P38422 — — 1 0.55 0.18 0.060.04 0.04 0.04 0.00 0.02 0.10 0.04 0.01 0.05 0.09 0.16 SEQID-00315P96600 — — 1 0.49 0.20 0.04 0.03 0.06 0.06 0.00 0.06 0.10 0.03 0.02 0.070.10 0.10 SEQID-00316 P39597 — — 1 0.47 0.16 0.05 0.05 0.04 0.07 0.010.07 0.06 0.05 0.02 0.04 0.09 0.11 SEQID-00317 Q9K6W0 — — 1 0.41 0.200.05 0.09 0.07 0.06 0.00 0.07 0.08 0.03 0.01 0.07 0.08 0.04 SEQID-00318O05512 — — 1 0.47 0.19 0.05 0.04 0.07 0.06 0.01 0.04 0.05 0.03 0.03 0.060.09 0.07 SEQID-00319 E6TXL6 — — 1 0.48 0.21 0.04 0.05 0.06 0.06 0.010.05 0.07 0.03 0.04 0.06 0.08 0.06 SEQID-00320 Q9K742 — — 1 0.42 0.180.03 0.14 0.04 0.06 0.00 0.02 0.13 0.03 0.03 0.06 0.08 0.07 SEQID-00321P37548 — — 1 0.49 0.22 0.04 0.08 0.03 0.06 0.01 0.05 0.07 0.03 0.05 0.070.08 0.10 SEQID-00322 O31526 — — 1 0.43 0.18 0.06 0.07 0.06 0.09 0.000.04 0.04 0.06 0.02 0.04 0.08 0.07 SEQID-00323 O07544 — — 1 0.48 0.200.03 0.07 0.02 0.05 0.02 0.06 0.06 0.03 0.03 0.07 0.09 0.10 SEQID-00324O32123 — — 1 0.44 0.16 0.03 0.07 0.02 0.04 0.01 0.08 0.10 0.02 0.04 0.040.09 0.06 SEQID-00325 P46784 — — 1 0.42 0.18 0.02 0.07 0.04 0.02 0.000.10 0.10 0.02 0.03 0.04 0.08 0.09 SEQID-00326 406713168 — — 1 0.44 0.190.03 0.08 0.02 0.03 0.02 0.09 0.10 0.02 0.02 0.04 0.10 0.05 SEQID-00327GAU

3 — — 1 0.53 0.25 0.04 0.04 0.05 0.07 0.00 0.02 0.08 0.03 0.02 0.09 0.100.12 SEQID-00328 291571454 — — 1 0.45 0.17 0.08 0.20 0.06 0.04 0.00 0.060.09 0.02 0.01 0.06 0.07 0.14 SEQID-00329 O82579 — — 1 0.47 0.22 0.020.20 0.03 0.04 0.01 0.03 0.05 0.02 0.04 0.05 0.06 0.12 SEQID-00330P0CX55 — — 1 0.49 0.22 0.03 0.15 0.06 0.05 0.01 0.06 0.05 0.03 0.06 0.070.10 0.08 SEQID-00331 P00648 — — 1 0.51 0.19 0.06 0.06 0.04 0.06 0.010.06 0.04 0.04 0.03 0.06 0.08 0.10 SEQID-00332 291572097 — — 1 0.45 0.220.06 0.09 0.03 0.09 0.00 0.05 0.07 0.03 0.03 0.05 0.13 0.04 SEQID-00333C3B4Y1 — — 1 0.52 0.23 0.02 0.05 0.06 0.04 0.01 0.04 0.05 0.02 0.03 0.070.11 0.10 SEQID-00334 C6TFG0 — — 1 0.42 0.21 0.04 0.18 0.04 0.05 0.000.04 0.08 0.03 0.03 0.03 0.11 0.03 SEQID-00335 291571495 — — 1 0.38 0.220.05 0.19 0.05 0.02 0.00 0.05 0.07 0.04 0.02 0.06 0.11 0.05 SEQID-0033694FL64 — — 1 0.46 0.15 0.06 0.19 0.02 0.02 0.00 0.03 0.07 0.02 0.03 0.040.07 0.18 SEQID-00337 IK8X7 — — 1 0.46 0.19 0.05 0.06 0.05 0.07 0.020.07 0.07 0.03 0.04 0.04 0.08 0.09 SEQID-00338 P07170 — — 1 0.47 0.210.06 0.06 0.04 0.09 0.00 0.06 0.06 0.04 0.03 0.07 0.10 0.10 SEQID-00339F0

I61 — — 1 0.47 0.21 0.04 0.06 0.06 0.09 0.00 0.03 0.09 0.03 0.05 0.060.11 0.09 SEQID-00340 406715507 — — 1 0.41 0.23 0.06 0.15 0.03 0.06 0.000.03 0.07 0.04 0.02 0.10 0.07 0.06 SEQID-00341 P29311 — — 1 0.39 0.180.06 0.06 0.03 0.05 0.01 0.03 0.13 0.02 0.03 0.05 0.09 0.07 SEQID-00342P33673 — — 1 0.47 0.15 0.06 0.06 0.07 0.07 0.01 0.04 0.05 0.04 0.01 0.040.08 0.10 SEQID-00343 I1LLC0 — — 1 0.46 0.22 0.05 0.10 0.04 0.07 0.010.03 0.10 0.02 0.05 0.06 0.09 0.10 SEQID-00344 291571381 — — 1 0.39 0.220.07 0.11 0.05 0.04 0.00 0.08 0.06 0.04 0.03 0.06 0.09 0.04 SEQID-00345291567248 — — 1 0.42 0.21 0.05 0.07 0.06 0.06 0.02 0.08 0.07 0.04 0.020.05 0.10 0.06 SEQID-00346 291569666 — — 1 0.45 0.21 0.07 0.07 0.03 0.050.01 0.05 0.10 0.05 0.03 0.05 0.09 0.07 SEQID-00347 H8XE54 — — 1 0.480.18 0.09 0.06 0.03 0.08 0.00 0.04 0.07 0.06 0.02 0.06 0.09 0.16SEQID-00348 B5DG39 — — 1 0.59 0.29 0.03 0.03 0.03 0.05 0.01 0.02 0.070.05 0.06 0.05 0.11 0.10 SEQID-00349 291567247 — — 1 0.45 0.21 0.03 0.090.04 0.07 0.01 0.04 0.08 0.06 0.05 0.05 0.10 0.05 SEQID-00350 P28675 — —1 0.49 0.27 0.03 0.05 0.09 0.04 0.02 0.04 0.07 0.06 0.03 0.07 0.14 0.08SEQID-00351 I1MJC7 — — 1 0.52 0.27 0.06 0.04 0.03 0.07 0.00 0.02 0.080.06 0.01 0.05 0.13 0.11 SEQID-00352 B4G0K4 — — 1 0.54 0.26 0.08 0.060.02 0.07 0.00 0.01 0.09 0.05 0.01 0.05 0.12 0.12 SEQID-00353 P45741 — —1 0.43 0.23 0.06 0.05 0.03 0.08 0.00 0.07 0.05 0.03 0.02 0.05 0.12 0.06SEQID-00354 B7TJ13 — — 1 0.52 0.23 0.06 0.04 0.05 0.06 0.02 0.02 0.070.05 0.02 0.05 0.10 0.12 SEQID-00355 P504

48 — — 1 0.51 0.24 0.04 0.06 0.03 0.06 0.01 0.05 0.06 0.036 0.03 0.050.14 0.06 SEQID-00356 I1MBR7 — — 1 0.50 0.27 0.04 0.06 0.07 0.06 0.000.06 0.09 0.04 0.02 0.07 0.12 0.09 SEQID-00357 291570796 — — 1 0.48 0.280.05 0.05 0.05 0.05 0.01 0.06 0.09 0.04 0.02 0.10 0.11 0.07 SEQID-00358291569660 — — 1 0.47 0.18 0.05 0.09 0.03 0.06 0.02 0.03 0.08 0.05 0.040.05 0.08 0.06 SEQID-00359 291566695 — — 1 0.42 0.23 0.06 0.14 0.03 0.070.00 0.07 0.07 0.03 0.03 0.07 0.11 0.04 SEQID-00360 Q42795 — — 1 0.450.21 0.04 0.05 0.06 0.07 0.01 0.05 0.07 0.04 0.03 0.05 0.09 0.07SEQID-00361 C5

V2 — — 1 0.44 0.20 0.04 0.10 0.04 0.05 0.01 0.07 0.09 0.06 0.03 0.050.08 0.07 SEQID-00362 P11412 — — 1 0.47 0.21 0.04 0.07 0.04 0.07 0.000.06 0.09 0.06 0.02 0.05 0.09 0.10 SEQID-00363 P69328 —  25:640 1 0.420.17 0.07 0.04 0.04 0.08 0.01 0.06 0.05 0.04 0.01 0.04 0.07 0.02SEQID-00364 F1NXK1 — 1220:1292 0 0.33 0.07 0.02 0.05 0.00 0.06 0.00 0.000.35 0.02 0.03 0.04 0.00 0.12 SEQID-00365 P02702 —  81:162 1 0.44 0.100.01 0.11 0.06 0.05 0.08 0.04 0.08 0.02 0.04 0.02 0.05 0.08 SEQID-00366P38158 — 118:186 0 0.48 0.07 0.03 0.09 0.07 0.06 0.00 0.02 0.06 0.030.00 0.01 0.04 0.09 SEQID-00367 Q12329 —  69:138 0 0.11 0.01 0.02 0.090.07 0.12 0.01 0.09 0.12 0.05 0.02 0.00 0.00 0.00 SEQID-00368 I

LP30 —  84:159 1 0.51 0.29 0.01 0.12 0.06 0.04 0.01 0.01 0.17 0.00 0.010.10 0.17 0.07 SEQID-00369 F1MZX6 — 1269:1337 0 0.48 0.23 0.06 0.04 0.030.06 0.00 0.20 0.12 0.01 0.05 0.06 0.17 0.11 SEQID-00370 I

KZL6 — 1621:1693 0 0.37 0.23 0.08 0.07 0.08 0.07 0.00 0.17 0.14 0.010.02 0.04 0.16 0.06 SEQID-00371 K7TNK3 — 1070:1154 1 0.36 0.18 0.05 0.080.01 0.04 0.00 0.16 0.24 0.01 0.05 0.03 0.12 0.05 SEQID-00372 291570621— 821:890 1 0.40 0.21 0.03 0.13 0.03 0.05 0.00 0.12 0.11 0.03 0.02 0.070.11 0.05 SEQID-00373 291572019 — 775:851 1 0.37 0.21 0.02 0.12 0.010.06 0.01 0.11 0.10 0.01 0.02 0.09 0.09 0.04 SEQID-00374 P38427 —534:617 1 0.44 0.21 0.02 0.17 0.02 0.06 0.01 0.10 0.06 0.02 0.03 0.040.09 0.05 SEQID-00375 A6QP89 — 288:356 0 0.45 0.21 0.04 0.19 0.01 0.060.00 0.03 0.06 0.03 0.00 0.06 0.08 0.13 SEQID-00376 I1JDH6 —  29:142 10.48 0.25 0.03 0.17 0.02 0.03 0.01 0.05 0.09 0.05 0.03 0.08 0.08 0.10SEQID-00377 406710335 —  6:235 0 0.37 0.17 0.04 0.03 0.02 0.03 0.01 0.250.19 0.01 0.02 0.02 0.11 0.06 SEQID-00378 I3JTN2 — 3518:3698 1 0.38 0.170.05 0.02 0.07 0.06 0.01 0.16 0.14 0.02 0.02 0.04 0.09 0.10 SEQID-00379F1NPH8 — 520:646 1 0.39 0.20 0.05 0.06 0.02 0.02 0.02 0.25 0.15 0.000.04 0.01 0.14 0.08 SEQID-00380 F1NPH8 — 673:746 1 0.43 0.25 0.04 0.110.04 0.03 0.02 0.06 0.20 0.01 0.02 0.03 0.20 0.07 SEQID-00381 G3MYN5 — 12:124 1 0.46 0.25 0.06 0.15 0.01 0.06 0.02 0.06 0.13 0.01 0.09 0.060.18 0.12 SEQID-00382 G3MYN5 —  88:158 1 0.50 0.23 0.03 0.19 0.01 0.030.00 0.00 0.08 0.02 0.02 0.01 0.14 0.17 SEQID-00383 C6TFG0 — 19:88 00.36 0.22 0.09 0.24 0.05 0.03 0.01 0.01 0.12 0.03 0.00 0.03 0.17 0.06SEQID-00384 C6TFG0 —  42:140 1 0.46 0.25 0.04 0.21 0.06 0.03 0.00 0.040.08 0.02 0.09 0.05 0.15 0.05 SEQID-00385 P

C0X0 — — 0 0.47 0.27 0.02 0.21 0.03 0.05 0.00 0.02 0.10 0.04 0.00 0.040.09 0.07 SEQID-00386 291568762 — — 0 0.39 0.26 0.03 0.08 0.03 0.06 0.000.10 0.08 0.02 0.00 0.07 0.12 0.05 SEQID-00387

4FKR5 — — 1 0.49 0.25 0.05 0.07 0.02 0.08 0.02 0.04 0.08 0.05 0.01 0.060.08 0.13 SEQID-00388

4FKR5 —  1:169 1 0.49 0.25 0.05 0.07 0.02 0.08 0.02 0.04 0.08 0.05 0.010.06 0.08 0.13 SEQID-00389 291567798 — — 0 0.44 0.26 0.04 0.13 0.05 0.020.01 0.05 0.08 0.06 0.01 0.06 0.08 0.11 SEQID-00390 P39824 —  37:306 10.48 0.22 0.07 0.06 0.07 0.08 0.00 0.02 0.06 0.03 0.01 0.08 0.09 0.11SEQID-00391 P39844 —  30:491 1 0.48 0.22 0.05 0.04 0.04 0.08 0.00 0.030.08 0.05 0.02 0.05 0.11 0.10 SEQID-00392 P96600 —  19:350 1 0.48 0.200.03 0.03 0.06 0.07 0.00 0.07 0.10 0.03 0.03 0.06 0.09 0.10 SEQID-00393P39597 —  29:416 1 0.47 0.17 0.05 0.05 0.05 0.07 0.01 0.07 0.06 0.050.02 0.04 0.09 0.11 SEQID-00394 O05512 —  27:362 1 0.45 0.17 0.05 0.040.07 0.07 0.01 0.05 0.05 0.04 0.03 0.06 0.08 0.06 SEQID-00395 P45741 — 31:409 1 0.41 0.22 0.06 0.06 0.03 0.08 0.00 0.07 0.06 0.03 0.02 0.050.11 0.05 SEQID-00396 P25959 —  29:124 1 0.45 0.21 0.01 0.10 0.03 0.030.01 0.10 0.12 0.03 0.02 0.07 0.10 0.09 SEQID-00397 P54450 —  45:250 10.50 0.16 0.03 0.04 0.08 0.05 0.01 0.03 0.05 0.04 0.04 0.06 0.08 0.13SEQID-00398 P37965 —  27:299 1 0.52 0.21 0.04 0.04 0.04 0.06 0.00 0.050.07 0.03 0.05 0.04 0.11 0.11 SEQID-00399 O34966 —  31:319 1 0.49 0.190.06 0.00 0.03 0.08 0.00 0.05 0.12 0.02 0.05 0.05 0.08 0.13 SEQID-00400P54427 —  24:267 1 0.52 0.19 0.03 0.07 0.04 0.08 0.00 0.05 0.08 0.030.03 0.05 0.08 0.10 SEQID-00401 P39632 —  31:154 1 0.51 0.25 0.04 0.070.04 0.07 0.00 0.04 0.07 0.04 0.01 0.06 0.11 0.07 SEQID-00402 O34348 — 29:315 1 0.50 0.22 0.04 0.05 0.06 0.09 0.00 0.02 0.09 0.03 0.03 0.070.08 0.14 SEQID-00403 P25152 —  25:455 1 0.46 0.20 0.07 0.04 0.04 0.050.00 0.04 0.10 0.04 0.03 0.07 0.08 0.11 SEQID-00404 P71014 —  29:181 10.49 0.18 0.06 0.06 0.08 0.03 0.01 0.02 0.06 0.03 0.01 0.03 0.12 0.03SEQID-00405 P94522 —  33:323 1 0.43 0.17 0.04 0.03 0.08 0.06 0.01 0.030.03 0.06 0.01 0.06 0.09 0.07 SEQID-00406 P54507 —  28:261 1 0.48 0.170.05 0.00 0.09 0.10 0.00 0.05 0.07 0.04 0.01 0.04 0.08 0.15 SEQID-00407P00691 —  34:659 1 0.42 0.16 0.05 0.05 0.09 0.083 0.00 0.05 0.04 0.040.03 0.06 0.06 0.06 SEQID-00408 A2QLC7 —  19:265 1 0.41 0.19 0.06 0.080.07 0.07 0.00 0.04 0.08 0.03 0.04 0.06 0.09 0.02 SEQID-00409 A2QEJ9 — 17:443 1 0.44 0.18 0.05 0.05 0.07 0.08 0.02 0.02 0.05 0.04 0.02 0.050.08 0.06 SEQID-00410 A2QXG2 —  21:338 1 0.49 0.25 0.05 0.04 0.06 0.060.00 0.05 0.06 0.03 0.02 0.08 0.12 0.04 SEQID-00411 A2QUK3 —  20:392 10.42 0.19 0.04 0.11 0.05 0.09 0.01 0.03 0.06 0.05 0.03 0.05 0.06 0.04SEQID-00412 A2QAC1 —  15:865 1 0.43 0.19 0.04 0.06 0.05 0.08 0.01 0.040.05 0.04 0.03 0.04 0.08 0.04 SEQID-00413 A2QJI1 —  18:375 1 0.44 0.180.05 0.04 0.08 0.08 0.02 0.04 0.04 0.03 0.02 0.03 0.10 0.04 SEQID-00414A2QAN3 —  19:1007 1 0.44 0.20 0.04 0.04 0.06 0.06 0.00 0.03 0.06 0.050.02 0.05 0.10 0.05 SEQID-00415 A2QWU9 —  22:931 1 0.45 0.20 0.04 0.060.05 0.07 0.00 0.05 0.05 0.04 0.03 0.05 0.09 0.04 SEQID-00416 A2QE24 — 24:403 1 0.45 0.22 0.04 0.04 0.07 0.06 0.01 0.07 0.05 0.05 0.02 0.080.07 0.04 SEQID-00417 A2QFV7 —  20:327 1 0.47 0.20 0.07 0.03 0.06 0.070.01 0.03 0.05 0.04 0.03 0.08 0.07 0.06 SEQID-00418 A2RAR6 —  23:416 10.43 0.16 0.06 0.05 0.04 0.03 0.01 0.07 0.04 0.05 0.03 0.03 0.07 0.04SEQID-00419 B0YIR9 —  20:860 1 0.39 0.18 0.06 0.06 0.07 0.07 0.01 0.040.07 0.06 0.01 0.04 0.08 0.04 SEQID-00420 A2QCV8 —  19:362 1 0.49 0.190.04 0.02 0.06 0.08 0.03 0.03 0.04 0.07 0.02 0.08 0.05 0.10 SEQID-00421P56526 —  20:985 1 0.43 0.19 0.06 0.05 0.06 0.06 0.01 0.05 0.05 0.040.03 0.04 0.08 0.03 SEQID-00422 A2QUZ1 —  20:458 1 0.38 0.15 0.06 0.050.06 0.09 0.01 0.02 0.05 0.05 0.00 0.03 0.06 0.07 SEQID-00423 P00692 — 32:514 1 0.43 0.15 0.04 0.06 0.05 0.03 0.00 0.05 0.07 0.05 0.04 0.040.06 0.07 SEQID-00424 P0C1B3 —  22:499 1 0.43 0.19 0.06 0.03 0.06 0.090.02 0.05 0.03 0.05 0.02 0.06 0.07 0.05 SEQID-00425 P00723 — — 1 0.470.19 0.03 0.05 0.06 0.07 0.01 0.03 0.09 0.03 0.04 0.05 0.07 0.09SEQID-00426 O59952 —  23:291 0 0.42 0.20 0.05 0.07 0.07 0.07 0.02 0.030.05 0.05 0.03 0.06 0.08 0.03 SEQID-00427 D4PHA8 — — 1 0.44 0.21 0.090.03 0.05 0.05 0.01 0.05 0.05 0.04 0.02 0.07 0.09 0.05 SEQID-00428P19515 —  95:363 0 0.55 0.00 0.02 0.04 0.01 0.14 0.00 0.06 0.13 0.010.02 0.00 0.00 0.16 SEQID-00429 P06278 — — 0 0.56 0.00 0.02 0.04 0.010.14 0.00 0.06 0.13 0.01 0.37 0.00 0.00 0.16 SEQID-00430 NA — 0 0.550.00 0.02 0.04 0.01 0.14 0.00 0.06 0.13 0.01 0.02 0.00 0.00 0.16SEQID-00431 NA — 0 0.56 0.00 0.02 0.04 0.01 0.14 0.00 0.06 0.13 0.010.37 0.00 0.00 0.16 SEQID-00432 NA — 0 0.55 0.00 0.02 0.04 0.01 0.140.00 0.06 0.13 0.01 0.02 0.00 0.00 0.50 SEQID-00433 NA — 0 0.20 0.000.02 0.42 0.01 0.13 0.00 0.06 0.12 0.01 0.02 0.00 0.00 0.15 SEQID-00434NA — 0 0.22 0.00 0.02 0.04 0.01 0.14 0.00 0.40 0.13 0.01 0.02 0.00 0.000.16 SEQID-00435 NA — 0 0.30 0.28 0.02 0.34 0.01 0.13 0.00 0.03 0.130.01 0.00 0.00 0.28 0.00 SEQID-00436 NA — 1 0.72 0.22 0.00 0.00 0.000.14 0.00 0.00 0.13 0.00 0.07 0.04 0.13 0.21 SEQID-00437 NA — 1 1.000.26 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.12 0.04 0.17 0.35SEQID-00438 NA — 0 0.53 0.31 0.02 0.04 0.01 0.15 0.00 0.07 0.13 0.010.02 0.12 0.19 0.17 SEQID-00439 NA — 0 0.53 0.30 0.02 0.04 0.02 0.150.00 0.07 0.14 0.01 0.02 0.00 0.19 0.17 SEQID-00440 NA — 0 0.55 0.180.02 0.04 0.01 0.14 0.00 0.06 0.13 0.01 0.02 0.00 0.18 0.16 SEQID-00441NA — 0 0.57 0.18 0.02 0.04 0.01 0.14 0.00 0.06 0.12 0.01 0.02 0.00 0.180.15 SEQID-00442 NA — 0 0.53 0.19 0.02 0.04 0.02 0.15 0.00 0.07 0.140.01 0.02 0.00 0.19 0.17 SEQID-00443 NA — 0 0.54 0.19 0.02 0.04 0.010.15 0.00 0.07 0.13 0.01 0.02 0.00 0.19 0.16 SEQID-00444 NA — 0 0.540.20 0.02 0.04 0.01 0.15 0.00 0.07 0.13 0.01 0.14 0.00 0.19 0.16SEQID-00445 NA — 0 0.41 0.19 0.02 0.04 0.01 0.15 0.00 0.20 0.13 0.010.02 0.00 0.19 0.16 SEQID-00446 NA — 0 0.32 0.28 0.02 0.27 0.01 0.140.00 0.06 0.13 0.01 0.00 0.00 0.28 0.00 SEQID-00447 NA — 0 0.58 0.190.02 0.00 0.01 0.15 0.00 0.07 0.13 0.01 0.00 0.00 0.19 0.35 SEQID-00448NA — 0 0.21 0.18 0.02 0.39 0.01 0.14 0.00 0.06 0.12 0.01 0.00 0.00 0.180.00 SEQID-00449 NA — 0 0.53 0.31 0.02 0.04 0.01 0.15 0.00 0.07 0.130.01 0.02 0.31 0.00 0.17 SEQID-00450 NA — 0 0.51 0.28 0.02 0.04 0.020.16 0.00 0.07 0.14 0.01 0.02 0.00 0.00 0.17 SEQID-00451 NA — 0 0.570.00 0.02 0.04 0.01 0.14 0.00 0.06 0.12 0.01 0.02 0.00 0.00 0.15SEQID-00452 NA — 0 0.61 0.00 0.02 0.03 0.01 0.12 0.00 0.06 0.11 0.010.01 0.00 0.00 0.14 SEQID-00453 NA — 0 0.52 0.00 0.02 0.04 0.02 0.150.00 0.07 0.14 0.01 0.02 0.00 0.00 0.17 SEQID-00454 NA — 0 0.59 0.280.00 0.41 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.28 0.30 SEQID-00455NA — 0 0.69 0.40 0.00 0.30 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.400.30 SEQID-00456 NA — 0 0.71 0.51 0.00 0.29 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.51 0.20 SEQID-00457 NA — 0 0.32 0.32 0.00 0.00 0.000.30 0.00 0.00 0.38 0.00 0.00 0.00 0.32 0.00 SEQID-00458 NA — 0 0.430.43 0.00 0.00 0.00 0.29 0.00 0.00 0.27 0.00 0.00 0.00 0.43 0.00SEQID-00459 NA — 0 0.55 0.55 0.00 0.00 0.00 0.20 0.00 0.00 0.26 0.000.00 0.00 0.55 0.00 SEQID-00460 NA — 0 0.41 0.30 0.00 0.25 0.00 0.150.00 0.00 0.19 0.00 0.00 0.00 0.30 0.12 SEQID-00461 NA — 0 0.49 0.400.00 0.27 0.00 0.12 0.00 0.00 0.12 0.00 0.00 0.00 0.40 0.08 SEQID-00462NA — 0 0.62 0.53 0.00 0.15 0.00 0.13 0.00 0.00 0.11 0.00 0.00 0.00 0.530.09 SEQID-00463 NA — 0 0.59 0.28 0.00 0.41 0.00 0.00 0.00 0.00 0.000.00 0.00 0.00 0.28 0.30 SEQID-00464 NA — 0 0.62 0.36 0.00 0.35 0.000.00 0.00 0.00 0.00 0.00 0.00 0.00 0.36 0.26 SEQID-00465 NA — 0 0.710.46 0.00 0.29 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.46 0.25SEQID-00466 NA — 0 0.32 0.32 0.00 0.00 0.00 0.30 0.00 0.00 0.38 0.000.00 0.00 0.32 0.00 SEQID-00467 NA — 0 0.40 0.40 0.00 0.00 0.00 0.260.00 0.00 0.34 0.00 0.00 0.00 0.40 0.00 SEQID-00468 NA — 0 0.50 0.500.00 0.00 0.00 0.24 0.00 0.00 0.26 0.00 0.00 0.00 0.50 0.00 SEQID-00469NA — 0 0.42 0.30 0.00 0.25 0.00 0.20 0.00 0.00 0.14 0.00 0.00 0.00 0.300.12 SEQID-00470 NA — 0 0.50 0.38 0.00 0.19 0.00 0.19 0.00 0.00 0.120.00 0.00 0.00 0.38 0.12 SEQID-00471 NA — 0 0.58 0.48 0.00 0.19 0.000.17 0.00 0.00 0.05 0.00 0.00 0.00 0.48 0.10 SEQID-00472 NA — 0 0.570.25 0.00 0.43 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.25 0.32SEQID-00473 NA — 0 0.75 0.37 0.00 0.24 0.00 0.00 0.00 0.00 0.00 0.000.00 0.00 0.37 0.38 SEQID-00474 NA — 0 0.67 0.46 0.00 0.32 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 0.46 0.22 SEQID-00475 NA — 0 0.28 0.280.00 0.00 0.00 0.32 0.00 0.00 0.39 0.00 0.00 0.00 0.28 0.00 SEQID-00476NA — 0 0.40 0.40 0.00 0.00 0.00 0.38 0.00 0.00 0.22 0.00 0.00 0.00 0.400.00 SEQID-00477 NA — 0 0.49 0.49 0.00 0.00 0.00 0.21 0.00 0.00 0.290.00 0.00 0.00 0.49 0.00 SEQID-00478 NA — 0 0.40 0.27 0.00 0.24 0.000.15 0.00 0.00 0.20 0.00 0.00 0.00 0.27 0.13 SEQID-00479 NA — 0 0.520.37 0.00 0.29 0.00 0.08 0.00 0.00 0.12 0.00 0.00 0.00 0.37 0.15SEQID-00480 NA — 0 0.62 0.48 0.00 0.11 0.00 0.16 0.00 0.00 0.11 0.000.00 0.00 0.48 0.14 SEQID-00481 K9HYS1 — 1 0.54 0.22 0.07 0.07 0.03 0.020.00 0.05 0.01 0.02 0.02 0.06 0.11 0.05 SEQID-00482 P39929 — 1 0.44 0.200.04 0.05 0.08 0.06 0.00 0.06 0.17 0.02 0.02 0.06 0.09 0.10 SEQID-00483F1MLW7 — 1 0.42 0.19 0.04 0.04 0.03 0.03 0.03 0.04 0.04 0.05 0.01 0.030.08 0.05 SEQID-00484 P17891 — 1 0.38 0.14 0.05 0.06 0.05 0.16 0.00 0.060.14 0.02 0.01 0.05 0.06 0.11 SEQID-00485 G1K3R9 — 1 0.46 0.16 0.05 0.060.06 0.08 0.01 0.00 0.05 0.04 0.01 0.06 0.06 0.09 SEQID-00486 O78750 — 10.56 0.27 0.02 0.04 0.02 0.04 0.01 0.03 0.07 0.02 0.03 0.08 0.14 0.03SEQID-00487 D5A2W2 — 1 0.61 0.27 0.03 0.05 0.00 0.02 0.01 0.03 0.04 0.040.03 0.09 0.09 0.05 SEQID-00488 K9HRR8 — 1 0.52 0.21 0.04 0.05 0.06 0.050.02 0.04 0.09 0.04 0.03 0.06 0.08 0.10 SEQID-00489 P07260 — 1 0.52 0.200.03 0.05 0.04 0.08 0.00 0.03 0.10 0.03 0.04 0.05 0.09 0.10 SEQID-00490K1WPG5 — 1 0.58 0.34 0.06 0.04 0.04 0.03 0.00 0.03 0.05 0.04 0.01 0.060.17 0.01 SEQID-00491 D7SYA1 — 1 0.46 0.15 0.06 0.19 0.03 0.02 0.00 0.030.07 0.02 0.03 0.03 0.07 0.18 SEQID-00492 D7SLS3 — 1 0.42 0.16 0.03 0.210.04 0.02 0.01 0.04 0.04 0.03 0.04 0.04 0.06 0.10 SEQID-00493 A5PJM2 — 10.42 0.14 0.04 0.15 0.02 0.06 0.02 0.05 0.14 0.02 0.04 0.02 0.09 0.12SEQID-00494 B9VGZ5 — 1 0.57 0.32 0.06 0.05 0.03 0.05 0.00 0.04 0.06 0.030.02 0.08 0.15 0.10 SEQID-00495 D7UC61 — 1 0.46 0.15 0.09 0.04 0.04 0.040.01 0.02 0.17 0.02 0.01 0.02 0.06 0.19 SEQID-00496 P52286 — 1 0.38 0.180.03 0.09 0.09 0.13 0.00 0.02 0.13 0.01 0.02 0.05 0.07 0.06 SEQID-00497P49435 — 0 0.50 0.26 0.07 0.03 0.04 0.04 0.01 0.04 0.11 0.04 0.01 0.070.14 0.09 SEQID-00498 K1VXA7 — 0 0.49 0.30 0.05 0.09 0.05 0.05 0.00 0.060.08 0.04 0.01 0.07 0.15 0.06 SEQID-00499 B6UI23 — 1 0.34 0.17 0.18 0.120.01 0.09 0.03 0.03 0.06 0.03 0.02 0.03 0.08 0.04 SEQID-00500 Q67VZ0 — 10.40 0.16 0.08 0.10 0.03 0.06 0.09 0.03 0.06 0.09 0.04 0.02 0.06 0.01SEQID-00501 K9HZV3 — 1 0.50 0.16 0.03 0.04 0.04 0.05 0.00 0.03 0.07 0.050.02 0.04 0.07 0.05 SEQID-00502 C6SZX7 — 1 0.48 0.20 0.06 0.03 0.09 0.070.02 0.03 0.06 0.04 0.01 0.04 0.09 0.12 SEQID-00503 B4FFR7 — 1 0.49 0.140.07 0.14 0.01 0.03 0.01 0.05 0.07 0.04 0.02 0.05 0.05 0.22 SEQID-00504K9HEB9 — 1 0.47 0.21 0.06 0.07 0.08 0.02 0.01 0.09 0.03 0.05 0.02 0.070.06 0.02 SEQID-00505 Q3SYR8 — 1 0.42 0.21 0.03 0.09 0.06 0.08 0.06 0.040.07 0.01 0.01 0.06 0.06 0.06 SEQID-00506 K9I599 — 1 0.62 0.29 0.07 0.030.02 0.02 0.00 0.02 0.04 0.03 0.05 0.11 0.12 0.05 SEQID-00507 K9HG54 — 10.51 0.14 0.06 0.03 0.04 0.06 0.00 0.02 0.07 0.02 0.00 0.03 0.06 0.10SEQID-00508 D7U394 — 1 0.54 0.25 0.05 0.04 0.03 0.05 0.03 0.03 0.07 0.060.03 0.05 0.07 0.08 SEQID-00509 Q3IJ07 — 1 0.43 0.13 0.03 0.13 0.03 0.080.00 0.05 0.17 0.02 0.03 0.04 0.07 0.19 SEQID-00510 G1NCP5 — 1 0.44 0.150.04 0.06 0.05 0.03 0.02 0.05 0.16 0.02 0.01 0.05 0.06 0.10 SEQID-00511K1WAW9 — 1 0.40 0.15 0.05 0.06 0.03 0.03 0.02 0.07 0.08 0.06 0.02 0.020.07 0.05 SEQID-00512 Q8H920 — 1 0.44 0.21 0.17 0.09 0.02 0.02 0.02 0.030.03 0.07 0.04 0.01 0.16 0.01 SEQID-00513 P06673 — 0 0.33 0.16 0.10 0.040.02 0.01 0.04 0.17 0.02 0.04 0.00 0.01 0.11 0.01 SEQID-00514 D4ZPH7 — 10.46 0.26 0.07 0.11 0.06 0.02 0.00 0.06 0.07 0.07 0.01 0.06 0.07 0.12SEQID-00515 Q08969 — 1 0.25 0.05 0.01 0.10 0.09 0.13 0.00 0.17 0.06 0.070.03 0.01 0.04 0.03 SEQID-00516 P04037 — 1 0.46 0.22 0.03 0.07 0.03 0.070.02 0.04 0.07 0.04 0.03 0.05 0.11 0.07 SEQID-00517 P04449 — 1 0.49 0.130.07 0.14 0.03 0.02 0.00 0.05 0.07 0.03 0.02 0.04 0.04 0.22 SEQID-00518FOTIG9 — 1 0.52 0.23 0.03 0.08 0.04 0.04 0.00 0.03 0.07 0.06 0.03 0.060.04 0.14 SEQID-00519 B6UD91 — 1 0.38 0.20 0.16 0.08 0.02 0.09 0.03 0.020.07 0.05 0.01 0.04 0.11 0.05 SEQID-00520 P63246 — 1 0.45 0.17 0.05 0.110.03 0.07 0.01 0.05 0.14 0.02 0.03 0.02 0.11 0.16 SEQID-00521 P72505 — 00.41 0.23 0.09 0.07 0.04 0.07 0.01 0.04 0.04 0.04 0.00 0.08 0.09 0.06SEQID-00522 O49817 — 0 0.40 0.03 0.10 0.04 0.03 0.08 0.00 0.17 0.08 0.040.02 0.01 0.01 0.16 SEQID-00523 K1X7Q4 — 0 0.51 0.19 0.04 0.05 0.05 0.000.00 0.06 0.08 0.04 0.00 0.05 0.12 0.04 SEQID-00524 P79395 — 1 0.48 0.190.03 0.06 0.07 0.01 0.00 0.02 0.08 0.02 0.04 0.04 0.06 0.10 SEQID-00525P01095 — 0 0.64 0.25 0.02 0.00 0.07 0.08 0.00 0.00 0.11 0.02 0.10 0.080.07 0.17 SEQID-00526 B1N67

— 0 0.41 0.13 0.06 0.17 0.03 0.01 0.10 0.02 0.08 0.04 0.02 0.01 0.070.03 SEQID-00527 D4ZQ

— 1 0.40 0.18 0.05 0.09 0.00 0.07 0.11 0.03 0.06 0.04 0.02 0.05 0.060.04 SEQID-00528 P38711 — 0 0.53 0.21 0.05 0.07 0.01 0.06 0.06 0.04 0.040.03 0.05 0.01 0.11 0.10 SEQID-00529 B2BN60 — 0 0.38 0.14 0.02 0.11 0.060.04 0.00 0.05 0.11 0.05 0.00 0.07 0.01 0.05 SEQID-00530 Q10ST8 — 0 0.370.20 0.13 0.10 0.04 0.01 0.10 0.05 0.00 0.08 0.01 0.02 0.07 0.04SEQID-00531 P14903 — 0 0.55 0.25 0.09 0.03 0.05 0.04 0.06 0.05 0.05 0.020.00 0.06 0.15 0.08 SEQID-00532 D4ZX53 — 0 0.44 0.28 0.06 0.10 0.02 0.030.00 0.02 0.11 0.05 0.02 0.09 0.03 0.03 SEQID-00533 D4ZPG3 — 0 0.47 0.230.04 0.15 0.03 0.06 0.00 0.05 0.08 0.01 0.00 0.05 0.08 0.08 SEQID-00534D4ZUU2 — 0 0.33 0.13 0.04 0.15 0.03 0.07 0.01 0.01 0.12 0.09 0.00 0.020.05 0.05 SEQID-00535 G5E604 — 0 0.30 0.16 0.06 0.10 0.06 0.04 0.02 0.080.02 0.06 0.00 0.04 0.06 0.00 SEQID-00536 O82575 — 0 0.58 0.10 0.09 0.000.00 0.04 0.00 0.01 0.20 0.04 0.23 0.04 0.05 0.18 SEQID-00537 Q08245 — 00.42 0.14 0.08 0.01 0.07 0.03 0.00 0.11 0.21 0.02 0.00 0.04 0.04 0.20SEQID-00538 F1P2P7 — 0 0.49 0.18 0.06 0.04 0.04 0.05 0.02 0.04 0.14 0.030.08 0.04 0.09 0.08 SEQID-00539 Q9N109 — 0 0.53 0.30 0.05 0.06 0.06 0.060.01 0.07 0.07 0.03 0.02 0.09 0.12 0.09 SEQID-00540 K1W1H1 — 0 0.41 0.210.05 0.23 0.02 0.06 0.00 0.03 0.05 0.05 0.01 0.06 0.08 0.08 SEQID-00541K9I1Y2 — 1 0.48 0.29 0.01 0.14 0.06 0.03 0.01 0.04 0.04 0.05 0.04 0.120.08 0.07 SEQID-00542 K9HG97 — 0 0.41 0.23 0.08 0.09 0.04 0.03 0.00 0.050.08 0.08 0.03 0.04 0.12 0.13 SEQID-00543 K9HDT0 — 1 0.42 0.16 0.03 0.110.06 0.06 0.02 0.04 0.06 0.04 0.01 0.05 0.05 0.04 SEQID-00544 Q5XQ56 — 00.45 0.20 0.12 0.06 0.01 0.07 0.00 0.07 0.06 0.03 0.05 0.04 0.11 0.06SEQID-00545 P00427 — 0 0.39 0.19 0.06 0.13 0.05 0.06 0.01 0.03 0.12 0.010.02 0.03 0.10 0.07 SEQID-00546 Q12513 — 0 0.39 0.20 0.04 0.07 0.09 0.110.01 0.03 0.12 0.03 0.02 0.08 0.07 0.08 SEQID-00547 E78SD7 — 0 0.49 0.090.08 0.04 0.04 0.03 0.00 0.04 0.10 0.08 0.08 0.01 0.01 0.12 SEQID-00548Q7YS10 — 1 0.59 0.27 0.03 0.00 0.03 0.05 0.02 0.09 0.12 0.04 0.03 0.080.13 0.11 SEQID-00549 P21306 — 0 0.40 0.15 0.12 0.07 0.05 0.02 0.00 0.080.04 0.02 0.00 0.05 0.07 0.08 SEQID-00550 D4ZT65 — 0 0.49 0.38 0.09 0.060.01 0.05 0.00 0.02 0.10 0.02 0.00 0.09 0.10 0.05 SEQID-00551 B6S

9 — 0 0.41 0.18 0.05 0.21 0.03 0.00 0.09 0.03 0.06 0.04 0.05 0.00 0.110.01 SEQID-00552 P50263 — 0 0.45 0.03 0.03 0.04 0.12 0.10 0.00 0.06 0.060.06 0.05 0.01 0.01 0.16 SEQID-00553 K6EQ38 — 0 0.39 0.05 0.08 0.00 0.000.07 0.00 0.01 0.15 0.00 0.01 0.01 0.00 0.23 SEQID-00554 K9H8H5 — 1 0.380.16 0.09 0.17 0.06 0.03 0.04 0.00 0.05 0.04 0.03 0.06 0.01 0.12SEQID-00555 D4ZXX9 — 0 0.45 0.26 0.03 0.17 0.02 0.02 0.00 0.07 0.09 0.040.01 0.12 0.04 0.08 SEQID-00556

4FEE7 — 0 0.33 0.13 0.08 0.22 0.05 0.04 0.05 0.03 0.03 0.04 0.06 0.040.02 0.03 SEQID-00557 G3MXD9 — 0 0.47 0.27 0.03 0.06 0.03 0.03 0.02 0.060.03 0.04 0.00 0.02 0.14 0.04 SEQID-00558 P53849 — 0 0.36 0.09 0.02 0.070.06 0.05 0.13 0.05 0.07 0.04 0.06 0.03 0.03 0.10 SEQID-00559 P0C030 — 00.50 0.26 0.03 0.07 0.02 0.08 0.00 0.07 0.10 0.04 0.02 0.11 0.11 0.11SEQID-00560 Q6PY61 — 0 0.55 0.10 0.02 0.00 0.02 0.13 0.00 0.01 0.12 0.070.18 0.08 0.01 0.26 SEQID-00561 D5A2Z0 — 1 0.68 0.36 0.03 0.02 0.03 0.020.01 0.02 0.03 0.06 0.03 0.18 0.14 0.04 SEQID-00562 F0TIX0 — 0 0.40 0.180.07 0.00 0.08 0.19 0.01 0.04 0.11 0.03 0.01 0.03 0.08 0.13 SEQID-00563Q65XV6 — 1 0.50 0.21 0.07 0.07 0.04 0.07 0.02 0.00 0.05 0.07 0.04 0.080.06 0.09 SEQID-00564 B6T878 — 0 0.51 0.17 0.09 0.05 0.02 0.03 0.00 0.020.09 0.03 0.02 0.07 0.06 0.22 SEQID-00565 D7UCH9 — 1 0.56 0.28 0.06 0.040.02 0.05 0.01 0.01 0.06 0.03 0.04 0.09 0.13 0.10 SEQID-00566 M1B8F8 — 00.38 0.15 0.04 0.02 0.04 0.03 0.11 0.02 0.07 0.06 0.03 0.05 0.07 0.08SEQID-00567 B4FUW2 — 1 0.42 0.17 0.03 0.22 0.04 0.02 0.01 0.05 0.04 0.040.04 0.03 0.07 0.10 SEQID-00568 B4FUS2 — 1 0.51 0.20 0.02 0.16 0.05 0.070.01 0.04 0.04 0.04 0.03 0.04 0.09 0.12 SEQID-00569 P02701 — 1 0.56 0.220.03 0.07 0.07 0.03 0.01 0.03 0.05 0.04 0.02 0.05 0.11 0.07 SEQID-00570P40185 — 0 0.48 0.23 0.07 0.05 0.09 0.03 0.01 0.04 0.06 0.01 0.03 0.040.08 0.08 SEQID-00571 P02074 — 0 0.54 0.25 0.08 0.06 0.05 0.05 0.01 0.020.07 0.05 0.06 0.00 0.13 0.07 SEQID-00572 M0ZHX8 — 0 0.54 0.17 0.06 0.050.02 0.02 0.00 0.02 0.10 0.03 0.02 0.07 0.05 0.23 SEQID-00573 Q9M3H6 — 00.54 0.17 0.08 0.05 0.02 0.02 0.00 0.02 0.10 0.02 0.02 0.07 0.04 0.23SEQID-00574 F0TIG5 — 0 0.44 0.19 0.04 0.14 0.05 0.03 0.00 0.03 0.03 0.050.04 0.04 0.07 0.12 SEQID-00575 B6SIA2 — 0 0.33 0.13 0.08 0.22 0.03 0.040.05 0.03 0.04 0.04 0.05 0.04 0.01 0.09 SEQID-00576 K9HNE7 — 1 0.42 0.210.09 0.04 0.06 0.07 0.06 0.05 0.00 0.04 0.03 0.03 0.05 0.04 SEQID-00577P02294 — 0 0.47 0.16 0.08 0.07 0.02 0.02 0.00 0.04 0.07 0.02 0.02 0.060.05 0.17 SEQID-00578 B6T2K5 — 0 0.54 0.22 0.05 0.15 0.01 0.02 0.00 0.040.06 0.01 0.02 0.05 0.13 0.21 SEQID-00579 B4FGQ6 — 0 0.47 0.19 0.03 0.170.02 0.01 0.01 0.06 0.04 0.03 0.02 0.04 0.07 0.18 SEQID-00580 F0TGC

— 1 0.49 0.15 0.08 0.16 0.04 0.04 0.00 0.04 0.02 0.03 0.02 0.04 0.070.16 SEQID-00581 D4ZPH2 — 0 0.51 0.21 0.02 0.12 0.03 0.04 0.00 0.04 0.070.04 0.03 0.04 0.04 0.15 SEQID-00582 K9I7W3 — 1 0.54 0.18 0.05 0.07 0.040.08 0.00 0.03 0.02 0.03 0.03 0.06 0.06 0.17 SEQID-00583 B6SGX0 — 0 0.560.18 0.05 0.16 0.01 0.02 0.00 0.01 0.06 0.05 0.04 0.03 0.09 0.21SEQID-00584 G3UV10 — 1 0.50 0.18 0.05 0.05 0.03 0.05 0.02 0.04 0.06 0.040.02 0.12 0.04 0.08 SEQID-00585 Q5BYT2 — 0 0.44 0.06 0.02 0.00 0.04 0.100.00 0.13 0.09 0.10 0.10 0.03 0.01 0.21 SEQID-00586 K1VX49 — 0 0.44 0.090.05 0.10 0.01 0.07 0.00 0.02 0.08 0.03 0.00 0.02 0.06 0.15 SEQID-00587P38910 — 0 0.51 0.29 0.06 0.04 0.05 0.07 0.00 0.07 0.06 0.04 0.00 0.070.11 0.12 SEQID-00588 K9HK97 — 1 0.44 0.20 0.04 0.17 0.04 0.01 0.00 0.030.09 0.05 0.02 0.07 0.06 0.11 SEQID-00589 Q12497 — 0 0.42 0.12 0.03 0.130.05 0.10 0.00 0.06 0.07 0.03 0.03 0.02 0.08 0.13 SEQID-00590 F0TEQ9 — 00.49 0.20 0.10 0.06 0.04 0.04 0.00 0.04 0.12 0.04 0.01 0.06 0.06 0.16SEQID-00591 P01098 — 0 0.37 0.18 0.04 0.14 0.09 0.03 0.01 0.06 0.10 0.030.03 0.06 0.10 0.11 SEQID-00592 B6SPL7 — 0 0.53 0.21 0.07 0.02 0.01 0.040.02 0.04 0.10 0.05 0.00 0.01 0.04 0.12 SEQID-00593 D5A0N7 — 1 0.49 0.200.05 0.08 0.01 0.04 0.00 0.08 0.07 0.04 0.01 0.11 0.06 0.03 SEQID-00594K4CBP6

— 0 0.44 0.14 0.05 0.16 0.03 0.01 0.09 0.01 0.07 0.03 0.03 0.03 0.060.04 SEQID-00595 K7WJX3 — 0 0.44 0.10 0.06 0.16 0.04 0.01 0.09 0.00 0.070.03 0.03 0.01 0.06 0.03 SEQID-00596 Q2I2W0 — 1 0.44 0.16 0.05 0.09 0.040.05 0.11 0.02 0.06 0.03 0.03 0.01 0.09 0.08 SEQID-00597 I1K554 — 0 0.450.18 0.03 0.19 0.00 0.05 0.10 0.05 0.03 0.05 0.03 0.01 0.12 0.06SEQID-00598 P82381 — 1 0.49 0.20 0.06 0.12 0.07 0.04 0.03 0.00 0.07 0.040.05 0.04 0.03 0.07 SEQID-00599 K9HN29 — 1 0.50 0.22 0.04 0.06 0.04 0.080.01 0.02 0.05 0.04 0.04 0.05 0.08 0.06 SEQID-00600 G1NGA7 — 1 0.50 0.210.06 0.06 0.02 0.02 0.02 0.04 0.06 0.04 0.01 0.05 0.09 0.08 SEQID-00601K9HJD1 — 1 0.40 0.14 0.06 0.05 0.03 0.05 0.02 0.09 0.09 0.05 0.06 0.040.07 0.09 SEQID-00602 F0TGH0 — 1 0.51 0.17 0.07 0.01 0.04 0.06 0.00 0.090.03 0.02 0.02 0.05 0.06 0.19 SEQID-00603 Q04491 — 1 0.51 0.22 0.05 0.040.04 0.06 0.01 0.03 0.09 0.04 0.05 0.05 0.08 0.08 SEQID-00604 K9HHN3 — 10.48 0.20 0.08 0.05 0.05 0.07 0.00 0.04 0.04 0.04 0.04 0.03 0.09 0.09SEQID-00605 K9I605 — 1 0.51 0.26 0.04 0.05 0.04 0.04 0.00 0.04 0.10 0.040.03 0.10 0.11 0.09 SEQID-00606 C6T9B1 — 1 0.48 0.20 0.06 0.07 0.05 0.030.01 0.02 0.08 0.05 0.12 0.06 0.09 0.05 SEQID-00607 K1WSX8 — 1 0.38 0.140.07 0.10 0.02 0.04 0.00 0.17 0.10 0.01 0.02 0.02 0.07 0.07 SEQID-00608Q3Z

I6 — 1 0.34 0.10 0.03 0.08 0.01 0.06 0.12 0.07 0.07 0.05 0.04 0.01 0.060.04 SEQID-00609 P39015 — 1 0.36 0.12 0.08 0.10 0.12 0.03 0.00 0.04 0.080.02 0.00 0.02 0.05 0.14 SEQID-00610 P38886 — 0 0.41 0.20 0.05 0.07 0.060.06 0.00 0.10 0.11 0.03 0.03 0.06 0.09 0.04 SEQID-00611 Q9FWV6 — 1 0.500.26 0.11 0.07 0.02 0.03 0.00 0.01 0.03 0.07 0.04 0.04 0.14 0.01SEQID-00612 Q6YTX5 — 1 0.42 0.25 0.16 0.06 0.02 0.04 0.00 0.02 0.06 0.030.04 0.03 0.12 0.05 SEQID-00613 K1WS36 — 0 0.36 0.19 0.08 0.08 0.07 0.040.00 0.13 0.13 0.02 0.00 0.04 0.11 0.08 SEQID-00614 K9H9H7 — 1 0.57 0.260.08 0.06 0.03 0.04 0.02 0.05 0.02 0.03 0.05 0.09 0.12 0.06 SEQID-00615F6HMP1 — 0 0.40 0.06 0.01 0.06 0.00 0.00 0.00 0.07 0.22 0.18 0.10 0.060.02 0.14 SEQID-00616 P05745 — 0 0.49 0.20 0.07 0.17 0.05 0.01 0.00 0.000.06 0.04 0.01 0.08 0.06 0.16 SEQID-00617 D4ZMN8 — 0 0.44 0.16 0.10 0.070.05 0.03 0.02 0.05 0.11 0.04 0.01 0.06 0.02 0.10 SEQID-00618 C6SWA6 — 00.46 0.23 0.08 0.11 0.04 0.02 0.00 0.02 0.06 0.07 0.02 0.04 0.11 0.17SEQID-00619

— 0 0.51 0.16 0.09 0.06 0.04 0.02 0.00 0.02 0.11 0.02 0.02 0.06 0.050.23 SEQID-00620 P48589 — 1 0.50 0.30 0.06 0.06 0.04 0.05 0.00 0.04 0.150.04 0.02 0.04 0.11 0.07 SEQID-00621 M1B1K7 — 0 0.39 0.22 0.08 0.11 0.060.02 0.00 0.04 0.06 0.03 0.02 0.05 0.11 0.10 SEQID-00622 Q0DT04 — 1 0.400.18 0.09 0.09 0.00 0.08 0.01 0.04 0.06 0.04 0.03 0.04 0.04 0.04SEQID-00623 O65819 — 0 0.54 0.17 0.08 0.05 0.02 0.03 0.00 0.03 0.09 0.020.02 0.07 0.05 0.23 SEQID-00624 D4ZXXG — 0 0.49 0.21 0.11 0.01 0.00 0.050.00 0.04 0.18 0.04 0.00 0.06 0.10 0.14 SEQID-00625 C66Y27 — 0 0.52 0.240.05 0.14 0.03 0.08 0.00 0.03 0.04 0.01 0.00 0.07 0.07 0.17 SEQID-00626F0TII3 — 1 0.46 0.26 0.05 0.09 0.06 0.06 0.00 0.02 0.07 0.04 0.01 0.120.06 0.11 SEQID-00627 Q62GV5 — 1 0.48 0.20 0.05 0.14 0.04 0.05 0.01 0.010.12 0.03 0.02 0.07 0.06 0.15 SEQID-00628 P38701 — 1 0.51 0.25 0.02 0.070.05 0.02 0.00 0.10 0.11 0.02 0.02 0.10 0.05 0.13 SEQID-00629 P39939 — 00.37 0.16 0.08 0.19 0.07 0.03 0.03 0.01 0.04 0.01 0.03 0.05 0.03 0.14SEQID-00630 G3N028 — 1 0.35 0.16 0.03 0.06 0.04 0.03 0.03 0.07 0.04 0.060.01 0.05 0.06 0.03 SEQID-00631 F0

3 — 0 0.38 0.20 0.04 0.21 0.04 0.09 0.01 0.02 0.06 0.04 0.01 0.07 0.060.10 SEQID-00632 P38804 — 0 0.47 0.20 0.05 0.03 0.07 0.04 0.00 0.02 0.140.06 0.00 0.05 0.08 0.13 SEQID-00633 P22943 — 0 0.35 0.10 0.08 0.04 0.030.11 0.00 0.07 0.12 0.06 0.02 0.01 0.03 0.16 SEQID-00634 Q3E792 — 0 0.500.21 0.08 0.09 0.00 0.04 0.00 0.05 0.05 0.02 0.03 0.08 0.08 0.19SEQID-00635 P41056 — 1 0.46 0.20 0.05 0.14 0.07 0.00 0.00 0.03 0.04 0.040.03 0.06 0.06 0.09 SEQID-00636

— 1 0.47 0.23 0.04 0.22 0.02 0.03 0.00 0.02 0.04 0.07 0.02 0.07 0.080.11 SEQID-00637 BGSGI4 — 1 0.42 0.07 0.06 0.22 0.04 0.00 0.04 0.01 0.020.05 0.04 0.03 0.02 0.12 SEQID-00638 D4ZUU9 — 0 0.48 0.21 0.06 0.11 0.030.03 0.00 0.04 0.14 0.02 0.00 0.04 0.07 0.14 SEQID-00639 P0CX26 — 1 0.460.16 0.08 0.15 0.00 0.01 0.05 0.04 0.04 0.05 0.01 0.04 0.03 0.14SEQID-00640 F0TIH8 — 0 0.47 0.19 0.01 0.13 0.06 0.05 0.00 0.02 0.06 0.010.03 0.04 0.02 0.16 SEQID-00641 P01097 — 0 0.39 0.14 0.04 0.17 0.01 0.050.00 0.03 0.12 0.03 0.01 0.02 0.09 0.10 SEQID-00642 Q01519 — 1 0.45 0.110.04 0.03 0.06 0.11 0.04 0.08 0.05 0.02 0.04 0.03 0.03 0.09 SEQID-00643D4P880 — 0 0.57 0.24 0.02 0.07 0.02 0.07 0.03 0.03 0.08 0.04 0.01 0.050.13 0.15 SEQID-00644 D5A1R0 — 0 0.42 0.22 0.06 0.09 0.07 0.04 0.01 0.040.09 0.04 0.00 0.05 0.03 0.09 SEQID-00645 P37299 — 1 0.56 0.20 0.03 0.040.03 0.04 0.00 0.01 0.05 0.05 0.05 0.01 0.17 0.07 SEQID-00646 B6UDM4 — 10.54 0.23 0.06 0.09 0.01 0.04 0.01 0.03 0.03 0.05 0.03 0.03 0.15 0.09SEQID-00647 K1XDJ4 — 0 0.42 0.24 0.04 0.15 0.04 0.04 0.00 0.09 0.12 0.010.05 0.05 0.18 0.08 SEQID-00648 K1WP04 — 1 0.39 0.12 0.03 0.19 0.03 0.060.00 0.00 0.17 0.04 0.03 0.04 0.04 0.08 SEQID-00649 Q6H6I1 — 1 0.42 0.190.13 0.08 0.02 0.04 0.03 0.01 0.06 0.05 0.03 0.05 0.06 0.05 SEQID-00650F1NXK2 — 0 0.50 0.23 0.04 0.11 0.02 0.08 0.00 0.00 0.09 0.04 0.00 0.080.03 0.07 SEQID-00651 B6UHQ3 — 1 0.39 0.19 0.17 0.03 0.01 0.06 0.02 0.070.04 0.04 0.05 0.01 0.13 0.02 SEQID-00652 P01064 — 0 0.28 0.08 0.00 0.030.02 0.13 0.16 0.05 0.03 0.01 0.01 0.02 0.06 0.07 SEQID-00653 E1UJV6 — 00.47 0.22 0.10 0.07 0.05 0.05 0.01 0.03 0.09 0.04 0.00 0.08 0.05 0.11SEQID-00654 E1USS1 — 1 0.54 0.28 0.07 0.05 0.04 0.06 0.00 0.03 0.09 0.030.05 0.11 0.11 0.07 SEQID-00655 E1UU33 — 0 0.47 0.21 0.07 0.06 0.05 0.060.01 0.05 0.13 0.04 0.02 0.06 0.08 0.12 SEQID-00656 E1UV85 — 0 0.44 0.200.07 0.01 0.06 0.05 0.00 0.14 0.07 0.04 0.00 0.05 0.06 0.13 SEQID-00657E1UR

2 — 1 0.49 0.17 0.05 0.02 0.09 0.07 0.00 0.04 0.07 0.04 0.01 0.05 0.070.13 SEQID-00658 E1URC8 — 1 0.42 0.17 0.06 0.04 0.06 0.09 0.00 0.07 0.090.04 0.01 0.05 0.07 0.16 SEQID-00659 E1UV03 — 1 0.44 0.17 0.05 0.06 0.100.05 0.00 0.05 0.05 0.03 0.04 0.05 0.05 0.05 SEQID-00660 E1UKZ8 — 1 0.480.17 0.06 0.02 0.083 0.09 0.00 0.04 0.08 0.04 0.02 0.04 0.08 0.14SEQID-00661 P00780 — 1 0.44 0.22 0.10 0.02 0.07 0.05 0.00 0.03 0.04 0.060.03 0.05 0.06 0.08 SEQID-00662 E1UMM6 — 1 0.43 0.17 0.04 0.04 0.08 0.060.01 0.02 0.04 0.06 0.01 0.06 0.08 0.07 SEQID-00663 QBGCB2 — 1 0.47 0.200.03 0.05 0.12 0.06 0.00 0.01 0.04 0.05 0.03 0.09 0.05 0.08 SEQID-00664Q65EF5 — 1 0.50 0.19 0.05 0.05 0.07 0.06 0.00 0.04 0.07 0.05 0.03 0.070.04 0.10 SEQID-00665 D5DEH5 — 1 0.41 0.17 0.06 0.03 0.07 0.07 0.00 0.040.04 0.05 0.02 0.04 0.06 0.09 SEQID-00666 G2RXU3 — 1 0.46 0.24 0.07 0.050.05 0.07 0.00 0.03 0.10 0.06 0.01 0.07 0.09 0.07 SEQID-00667 E1UPU6 — 10.40 0.15 0.05 0.09 0.05 0.11 0.00 0.04 0.07 0.04 0.01 0.03 0.07 0.10SEQID-00668 E1UQB7 — 1 0.52 0.16 0.05 0.01 0.03 0.10 0.00 0.05 0.09 0.030.01 0.03 0.08 0.23 SEQID-00669 P07170 — 1 0.48 0.21 0.06 0.06 0.04 0.090.00 0.06 0.06 0.04 0.03 0.07 0.10 0.10 SEQID-00670 P07170 — 1 0.48 0.210.06 0.06 0.04 0.09 0.00 0.06 0.06 0.04 0.03 0.07 0.10 0.10 SEQID-00671P07170 — 1 0.48 0.21 0.06 0.05 0.04 0.09 0.00 0.06 0.06 0.04 0.03 0.070.10 0.10 SEQID-00672 P07170 — 1 0.47 0.21 0.06 0.06 0.04 0.09 0.00 0.060.06 0.04 0.03 0.07 0.10 0.10 SEQID-00673 P07170 — 1 0.47 0.21 0.06 0.050.04 0.09 0.00 0.06 0.06 0.04 0.03 0.07 0.10 0.10 SEQID-00674 P07170 — 10.47 0.21 0.07 0.05 0.04 0.09 0.00 0.06 0.06 0.04 0.03 0.07 0.10 0.10SEQID-00675 P07170 — 1 0.47 0.21 0.06 0.05 0.04 0.09 0.01 0.06 0.06 0.040.03 0.07 0.10 0.10 SEQID-00676 P07170 — 1 0.47 0.21 0.06 0.05 0.04 0.090.00 0.06 0.06 0.04 0.03 0.07 0.10 0.10 SEQID-00677 P07170 — 1 0.48 0.210.06 0.05 0.04 0.09 0.00 0.06 0.06 0.04 0.03 0.07 0.10 0.10 SEQID-00678P07170 — 1 0.48 0.21 0.06 0.05 0.04 0.09 0.00 0.06 0.06 0.04 0.03 0.070.10 0.11 SEQID-00679 P07170 — 1 0.48 0.21 0.06 0.05 0.04 0.09 0.00 0.060.06 0.04 0.03 0.07 0.10 0.10 SEQID-00680 P07170 — 1 0.47 0.21 0.06 0.050.04 0.09 0.00 0.06 0.06 0.04 0.03 0.07 0.10 0.10 SEQID-00681 P07170 — 10.48 0.21 0.06 0.05 0.04 0.09 0.00 0.06 0.06 0.04 0.03 0.07 0.10 0.10SEQID-00682 P07170 — 1 0.48 0.21 0.06 0.05 0.04 0.09 0.00 0.06 0.06 0.040.03 0.07 0.10 0.10 SEQID-00683 P00691  34:659 1 0.43 0.16 0.05 0.050.09 0.03 0.00 0.05 0.04 0.04 0.03 0.06 0.06 0.06 SEQID-00684 P00691 34:659 1 0.44 0.17 0.05 0.05 0.09 0.07 0.00 0.05 0.04 0.05 0.03 0.060.06 0.06 SEQID-00685 P00691  34:659 1 0.43 0.16 0.05 0.05 0.09 0.080.00 0.05 0.04 0.05 0.03 0.05 0.06 0.06 SEQID-00686 P00691  34:659 10.43 0.16 0.05 0.05 0.09 0.08 0.00 0.05 0.04 0.05 0.03 0.05 0.06 0.06SEQID-00687 P00691  34:659 1 0.42 0.16 0.05 0.05 0.09 0.07 0.00 0.050.04 0.04 0.03 0.06 0.06 0.06 SEQID-00688 P00691  34:659 1 0.43 0.160.05 0.05 0.09 0.07 0.00 0.05 0.04 0.05 0.03 0.05 0.06 0.06 SEQID-00689P00691  34:659 1 0.43 0.16 0.05 0.05 0.09 0.08 0.00 0.05 0.04 0.05 0.030.05 0.06 0.06 SEQID-00690 P00691  34:659 1 0.44 0.17 0.05 0.05 0.090.07 0.00 0.05 0.04 0.05 0.03 0.06 0.06 0.06 SEQID-00691 P00691  34:6591 0.44 0.17 0.05 0.05 0.09 0.07 0.00 0.05 0.04 0.05 0.03 0.06 0.06 0.06SEQID-00692 P00691  34:659 1 0.44 0.17 0.05 0.05 0.09 0.07 0.00 0.050.04 0.05 0.03 0.06 0.07 0.06 SEQID-00693 P00691  34:659 1 0.44 0.160.05 0.05 0.09 0.07 0.00 0.05 0.04 0.05 0.03 0.05 0.06 0.06 SEQID-00694P00691  34:659 1 0.43 0.16 0.05 0.05 0.09 0.08 0.00 0.05 0.04 0.05 0.030.06 0.06 0.06 SEQID-00695 P00691  34:659 1 0.43 0.16 0.05 0.05 0.090.08 0.00 0.05 0.04 0.05 0.03 0.05 0.06 0.06 SEQID-00696 P00691  34:6591 0.44 0.17 0.05 0.05 0.09 0.07 0.00 0.05 0.04 0.05 0.03 0.06 0.06 0.06SEQID-00697 P00691  34:659 1 0.43 0.17 0.05 0.05 0.09 0.07 0.00 0.050.04 0.05 0.03 0.06 0.06 0.06 SEQID-00698 P00691  34:659 1 0.44 0.170.05 0.05 0.09 0.07 0.00 0.05 0.04 0.05 0.03 0.06 0.06 0.06 SEQID-00699P00691  34:659 1 0.43 0.16 0.05 0.05 0.09 0.07 0.00 0.05 0.04 0.05 0.030.05 0.06 0.06 SEQID-00700 P00691  34:659 1 0.44 0.17 0.05 0.05 0.090.07 0.00 0.05 0.04 0.05 0.03 0.06 0.06 0.06 SEQID-00701 P00691  34:6591 0.44 0.17 0.05 0.05 0.09 0.07 0.00 0.05 0.04 0.05 0.03 0.06 0.06 0.06SEQID-00702 P00691  34:659 1 0.44 0.17 0.05 0.05 0.09 0.07 0.00 0.050.04 0.05 0.03 0.06 0.06 0.06 SEQID-00703 P00691  34:659 1 0.43 0.160.05 0.05 0.09 0.07 0.00 0.05 0.04 0.05 0.03 0.06 0.06 0.06 SEQID-00704P00691  34:659 1 0.43 0.17 0.05 0.06 0.09 0.07 0.00 0.05 0.04 0.05 0.030.06 0.06 0.06 SEQID-00705 P00691  34:659 1 0.44 0.17 0.05 0.05 0.090.07 0.00 0.05 0.04 0.05 0.03 0.05 0.06 0.06 SEQID-00706 P00691  34:6591 0.42 0.16 0.05 0.05 0.09 0.08 0.00 0.06 0.04 0.05 0.03 0.05 0.05 0.06SEQID-00707 P00691  34:659 1 0.42 0.16 0.05 0.05 0.09 0.08 0.00 0.060.04 0.05 0.03 0.05 0.05 0.06 SEQID-00708 P00691  34:659 1 0.42 0.160.05 0.05 0.09 0.08 0.00 0.06 0.04 0.05 0.03 0.05 0.05 0.06 SEQID-00709P00691  34:659 1 0.42 0.16 0.05 0.05 0.09 0.08 0.00 0.06 0.04 0.05 0.030.05 0.05 0.06 SEQID-00710 P00691  34:659 1 0.42 0.16 0.05 0.05 0.090.07 0.00 0.05 0.04 0.04 0.03 0.06 0.06 0.06 SEQID-00711 P00691  34:6591 0.43 0.16 0.05 0.05 0.09 0.06 0.00 0.05 0.04 0.04 0.03 0.06 0.06 0.06SEQID-00712 P00691  34:659 1 0.42 0.16 0.05 0.05 0.09 0.08 0.00 0.050.04 0.04 0.03 0.06 0.06 0.06 SEQID-00713 P00691  34:659 1 0.42 0.160.05 0.05 0.09 0.08 0.00 0.05 0.04 0.04 0.03 0.06 0.06 0.06 SEQID-00714P00691  34:659 1 0.43 0.16 0.05 0.05 0.09 0.08 0.00 0.05 0.04 0.04 0.030.06 0.06 0.06 SEQID-00715 P00691  34:659 1 0.43 0.16 0.05 0.05 0.090.08 0.00 0.05 0.04 0.04 0.03 0.06 0.06 0.06 SEQID-00716 E7Q265 — 1 0.460.20 0.06 0.07 0.04 0.09 0.01 0.06 0.07 0.04 0.03 0.07 0.10 0.10SEQID-00717 E1BKT9 — 1 0.41 0.20 0.03 0.10 0.04 0.06 0.01 0.09 0.12 0.030.02 0.06 0.10 0.09 SEQID-00718 W5Q7Z7 — 1 0.42 0.20 0.03 0.10 0.04 0.060.01 0.09 0.12 0.02 0.02 0.06 0.11 0.10 SEQID-00719 F1RW75 — 1 0.41 0.200.04 0.10 0.04 0.06 0.01 0.09 0.12 0.02 0.02 0.06 0.10 0.10 SEQID-00720Q8SPI1 — 1 0.45 0.24 0.06 0.07 0.05 0.05 0.02 0.06 0.07 0.03 0.03 0.050.13 0.05 SEQID-00721 Q6PVZ5 — 1 0.38 0.19 0.05 0.10 0.04 0.04 0.00 0.050.09 0.10 0.01 0.04 0.10 0.06 SEQID-00722 E7Q6N3 — 0 0.53 0.26 0.01 0.070.02 0.07 0.00 0.08 0.08 0.04 0.01 0.09 0.12 0.11 SEQID-00723 E7Q6P3 — 00.43 0.23 0.05 0.03 0.04 0.08 0.01 0.07 0.10 0.03 0.02 0.08 0.11 0.09SEQID-00724 E7Q142 — 1 0.53 0.20 0.06 0.03 0.07 0.05 0.00 0.04 0.07 0.040.04 0.06 0.09 0.03 SEQID-00725 Q28161 — 1 0.38 0.16 0.05 0.10 0.06 0.050.03 0.06 0.05 0.04 0.02 0.03 0.10 0.06 SEQID-00726 P53478 — 1 0.47 0.200.05 0.07 0.02 0.06 0.01 0.04 0.09 0.04 0.03 0.08 0.07 0.06 SEQID-00727A25W69 — 1 0.45 0.21 0.04 0.03 0.03 0.09 0.01 0.04 0.08 0.03 0.01 0.060.10 0.11 SEQID-00728 F1S3U9 — 1 0.51 0.21 0.04 0.05 0.03 0.08 0.01 0.050.05 0.04 0.02 0.09 0.06 0.11 SEQID-00729 E7Q765 — 1 0.40 0.18 0.04 0.030.07 0.06 0.01 0.04 0.17 0.02 0.03 0.05 0.06 0.09 SEQID-00730 E7Q9J9 — 10.51 0.23 0.04 0.04 0.05 0.06 0.02 0.04 0.07 0.04 0.03 0.07 0.09 0.10SEQID-00731 F1SGG1 — 1 0.40 0.23 0.05 0.11 0.04 0.06 0.00 0.07 0.12 0.030.02 0.05 0.13 0.06 SEQID-00732 Q03763 — 1 0.43 0.22 0.03 0.07 0.07 0.050.02 0.03 0.07 0.06 0.02 0.07 0.07 0.04 SEQID-00733 F1STM4 — 1 0.52 0.210.06 0.06 0.04 0.05 0.01 0.03 0.07 0.04 0.03 0.07 0.06 0.11 SEQID-00734E7Q5T7 — 1 0.42 0.19 0.03 0.05 0.07 0.06 0.00 0.06 0.16 0.01 0.02 0.050.11 0.11 SEQID-00735 E7Q880 — 1 0.44 0.21 0.06 0.06 0.04 0.06 0.01 0.100.09 0.01 0.03 0.06 0.11 0.07 SEQID-00736 K4BLT8 — 1 0.48 0.25 0.05 0.050.04 0.07 0.02 0.04 0.07 0.03 0.02 0.08 0.09 0.08 SEQID-00737 F1SFT0 — 00.28 0.09 0.02 0.04 0.02 0.03 0.18 0.11 0.00 0.04 0.00 0.01 0.02 0.06SEQID-00738 I3LK01 — 1 0.38 0.20 0.06 0.11 0.04 0.03 0.03 0.06 0.13 0.030.02 0.05 0.09 0.07 SEQID-00739 ASD984 — 1 0.48 0.23 0.07 0.08 0.04 0.060.02 0.03 0.08 0.04 0.03 0.08 0.08 0.08 SEQID-00740 E7Q1Q3 — 0 0.48 0.230.03 0.06 0.03 0.07 0.01 0.04 0.11 0.04 0.02 0.07 0.11 0.12 SEQID-00741E7Q1V1 — 1 0.39 0.21 0.02 0.10 0.07 0.06 0.01 0.08 0.09 0.02 0.03 0.060.12 0.05 SEQID-00742 I1N6A2 — 1 0.43 0.22 0.05 0.11 0.04 0.06 0.00 0.060.10 0.03 0.02 0.07 0.10 0.07 SEQID-00743 P35323 — 0 0.29 0.08 0.01 0.000.00 0.00 0.09 0.22 0.08 0.00 0.03 0.01 0.00 0.14 SEQID-00744 F1SAM0 — 10.46 0.20 0.03 0.05 0.04 0.07 0.03 0.05 0.08 0.04 0.03 0.05 0.09 0.08SEQID-00745 F1SGS9 — 1 0.43 0.16 0.05 0.08 0.06 0.07 0.01 0.05 0.06 0.030.05 0.04 0.06 0.06 SEQID-00746 I3LR13 — 1 0.40 0.19 0.04 0.11 0.02 0.040.01 0.07 0.09 0.03 0.04 0.02 0.12 0.02 SEQID-00747 P0C522 — 0 0.42 0.250.07 0.09 0.04 0.05 0.01 0.06 0.08 0.04 0.01 0.07 0.10 0.06 SEQID-00748Q6K838 — 1 0.46 0.23 0.05 0.09 0.03 0.04 0.01 0.07 0.06 0.03 0.02 0.050.12 0.07 SEQID-00749 Q2KJ64 — 1 0.51 0.24 0.03 0.05 0.02 0.07 0.01 0.020.08 0.05 0.03 0.06 0.10 0.10 SEQID-00750 F1MUE4 — 1 0.49 0.24 0.04 0.070.03 0.05 0.01 0.05 0.12 0.03 0.02 0.02 0.16 0.08 SEQID-00751 E1BLN6 — 10.23 0.12 0.02 0.11 0.01 0.02 0.10 0.10 0.06 0.03 0.01 0.02 0.04 0.03SEQID-00752 E7Q207 — 1 0.48 0.20 0.06 0.07 0.04 0.04 0.00 0.03 0.11 0.030.01 0.05 0.08 0.11 SEQID-00753 E7QAF4 — 1 0.51 0.28 0.03 0.04 0.07 0.080.01 0.04 0.07 0.02 0.02 0.09 0.15 0.09 SEQID-00754 D7TRY0 — 1 0.37 0.130.04 0.06 0.05 0.05 0.00 0.03 0.19 0.03 0.01 0.03 0.05 0.14 SEQID-00755Q9SWB6 — 1 0.50 0.20 0.05 0.04 0.04 0.04 0.02 0.04 0.12 0.03 0.02 0.060.09 0.09 SEQID-00756 W5P481 — 1 0.24 0.10 0.07 0.08 0.02 0.05 0.01 0.050.06 0.15 0.01 0.02 0.04 0.05 SEQID-00757 W5PVF9 — 1 0.37 0.15 0.04 0.090.05 0.06 0.02 0.05 0.08 0.03 0.04 0.03 0.07 0.06 SEQID-00758 F15GP9 — 10.41 0.19 0.03 0.10 0.05 0.06 0.02 0.04 0.07 0.05 0.03 0.04 0.07 0.04SEQID-00759 F15II1 — 1 0.45 0.17 0.03 0.02 0.06 0.04 0.01 0.05 0.13 0.050.02 0.06 0.05 0.13 SEQID-00760 Q3SYU2 — 1 0.48 0.22 0.05 0.07 0.03 0.060.02 0.04 0.08 0.04 0.02 0.06 0.09 0.09 SEQID-00761 F1MW

0 — 1 0.30 0.18 0.02 0.03 0.02 0.02 0.03 0.05 0.01 0.12 0.02 0.05 0.070.04 SEQID-00762 P02075 — 0 0.56 0.23 0.07 0.04 0.06 0.06 0.01 0.03 0.060.04 0.08 0.00 0.12 0.10 SEQID-00763 P60706 — 1 0.47 0.20 0.05 0.07 0.020.06 0.01 0.04 0.03 0.04 0.03 0.08 0.07 0.06 SEQID-00764 P01966 — 0 0.560.23 0.09 0.03 0.02 0.06 0.00 0.01 0.04 0.03 0.09 0.00 0.15 0.09SEQID-00765 F1MKE9 — 1 0.43 0.19 0.05 0.09 0.03 0.07 0.01 0.08 0.12 0.020.03 0.04 0.11 0.07 SEQID-00766

H7U1 — 1 0.43 0.17 0.04 0.07 0.05 0.07 0.02 0.05 0.09 0.04 0.03 0.030.08 0.04 SEQID-00767 O64937 — 1 0.52 0.21 0.04 0.06 0.04 0.06 0.01 0.020.08 0.04 0.03 0.07 0.06 0.13 SEQID-00768 K7LZH1 — 1 0.45 0.21 0.06 0.070.05 0.08 0.01 0.04 0.10 0.04 0.01 0.08 0.07 0.09 SEQID-00769 O77642 — 10.39 0.18 0.07 0.07 0.03 0.06 0.01 0.04 0.16 0.03 0.01 0.04 0.10 0.08SEQID-00770 P28752 — 1 0.44 0.21 0.05 0.07 0.04 0.07 0.02 0.03 0.09 0.040.04 0.06 0.08 0.05 SEQID-00771 F6H7U7 — 1 0.43 0.21 0.06 0.08 0.05 0.060.01 0.05 0.11 0.02 0.02 0.05 0.11 0.09 SEQID-00772 F6HN28 — 1 0.44 0.210.05 0.09 0.03 0.06 0.01 0.04 0.12 0.02 0.03 0.06 0.11 0.06 SEQID-00773W5PC91 — 1 0.42 0.19 0.05 0.09 0.04 0.08 0.01 0.08 0.14 0.02 0.03 0.040.12 0.08 SEQID-00774 C7IZV3 — 1 0.44 0.20 0.04 0.15 0.02 0.05 0.03 0.030.05 0.04 0.05 0.06 0.08 0.06 SEQID-00775 E1C4S8 — 1 0.42 0.19 0.06 0.080.04 0.05 0.02 0.10 0.08 0.03 0.05 0.02 0.11 0.10 SEQID-00776 G3MXL3 — 10.37 0.18 0.05 0.08 0.04 0.04 0.01 0.06 0.08 0.12 0.01 0.04 0.09 0.06SEQID-00777 F1SKJ1 — 1 0.42 0.19 0.06 0.09 0.04 0.05 0.01 0.08 0.15 0.020.02 0.04 0.11 0.11 SEQID-00778 F1SSA6 — 1 0.42 0.19 0.06 0.09 0.04 0.050.01 0.09 0.16 0.02 0.02 0.04 0.11 0.11 SEQID-00779 F1SSS0 — 1 0.49 0.230.05 0.05 0.05 0.05 0.01 0.04 0.08 0.04 0.02 0.07 0.09 0.08 SEQID-00780P02663 — 1 0.47 0.18 0.03 0.04 0.06 0.02 0.01 0.08 0.12 0.00 0.02 0.050.07 0.12 SEQID-00781 G1NEY4 — 1 0.38 0.19 0.05 0.10 0.04 0.04 0.00 0.050.09 0.10 0.01 0.04 0.10 0.06 SEQID-00782 P02543 — 1 0.37 0.19 0.04 0.130.05 0.06 0.00 0.08 0.13 0.01 0.02 0.03 0.12 0.05 SEQID-00783 K4CAJ3 — 10.45 0.20 0.04 0.10 0.04 0.06 0.02 0.03 0.10 0.03 0.03 0.06 0.08 0.06SEQID-00784 E7Q2C6 — 1 0.47 0.25 0.05 0.10 0.04 0.08 0.01 0.04 0.09 0.030.02 0.07 0.11 0.10 SEQID-00785 P68103 — 1 0.51 0.21 0.06 0.05 0.04 0.060.01 0.03 0.07 0.05 0.03 0.07 0.06 0.12 SEQID-00786 Q04619 — 1 0.47 0.200.03 0.06 0.04 0.07 0.01 0.03 0.15 0.02 0.02 0.06 0.08 0.12 SEQID-00787P31691 — 1 0.45 0.18 0.07 0.08 0.05 0.05 0.01 0.04 0.03 0.07 0.00 0.050.08 0.08 SEQID-00788 P00829 — 0 0.45 0.26 0.08 0.07 0.02 0.06 0.00 0.060.08 0.05 0.02 0.07 0.10 0.05 SEQID-00789 Q0IWN2 — 1 0.47 0.21 0.09 0.090.04 0.04 0.01 0.03 0.11 0.02 0.03 0.04 0.12 0.11 SEQID-00790 P0C276 — 00.49 0.22 0.02 0.11 0.05 0.05 0.04 0.07 0.06 0.03 0.03 0.03 0.10 0.15SEQID-00791 E1B9D0 — 1 0.389 0.21 0.07 0.14 0.02 0.05 0.01 0.05 0.080.04 0.03 0.02 0.14 0.02 SEQID-00792 E1BXJ2 — 1 0.47 0.21 0.03 0.03 0.050.05 0.01 0.07 0.10 0.02 0.03 0.06 0.11 0.09 SEQID-00793 I1JFH4 — 1 0.500.20 0.05 0.03 0.03 0.05 0.01 0.03 0.11 0.02 0.03 0.04 0.09 0.09SEQID-00794 I1NGL1 — 1 0.42 0.20 0.04 0.08 0.05 0.06 0.03 0.03 0.09 0.020.03 0.05 0.11 0.08 SEQID-00795 I3JQE4 — 1 0.48 0.24 0.06 0.05 0.03 0.050.02 0.06 0.08 0.03 0.03 0.05 0.13 0.08 SEQID-00796 W5NX33 — 1 0.47 0.230.04 0.07 0.05 0.05 0.02 0.04 0.08 0.02 0.05 0.06 0.10 0.05 SEQID-00797E7Q6A3 — 1 0.46 0.22 0.02 0.05 0.10 0.05 0.02 0.05 0.11 0.02 0.01 0.050.13 0.12 SEQID-00798 E7Q9U4 — 1 0.45 0.21 0.04 0.04 0.05 0.06 0.01 0.050.10 0.03 0.01 0.05 0.08 0.07 SEQID-00799 E7Q306 — 1 0.48 0.22 0.04 0.050.07 0.07 0.01 0.03 0.06 0.04 0.03 0.06 0.10 0.09 SEQID-00800 E7BQS1 — 10.46 0.16 0.03 0.04 0.06 0.02 0.01 0.03 0.12 0.00 0.03 0.05 0.06 0.12SEQID-00801 I1LP26 — 1 0.49 0.17 0.03 0.05 0.05 0.083 0.01 0.04 0.070.02 0.03 0.05 0.07 0.17 SEQID-00802 Q148H5 — 1 0.38 0.20 0.05 0.09 0.050.05 0.02 0.05 0.10 0.04 0.01 0.05 0.10 0.08 SEQID-00803 P04653 — 1 0.420.21 0.04 0.04 0.05 0.03 0.00 0.03 0.11 0.02 0.02 0.06 0.11 0.08SEQID-00804 E7QAF7 — 1 0.48 0.21 0.06 0.05 0.03 0.07 0.01 0.04 0.09 0.040.01 0.07 0.08 0.12 SEQID-00805 P11839 — 1 0.50 0.26 0.02 0.02 0.02 0.020.00 0.11 0.10 0.01 0.03 0.05 0.12 0.07 SEQID-00806 E7Q3D2 — 1 0.47 0.210.04 0.07 0.02 0.05 0.01 0.04 0.08 0.04 0.03 0.08 0.07 0.06 SEQID-00807E7Q6T4 — 1 0.50 0.24 0.03 0.06 0.06 0.07 0.01 0.03 0.07 0.02 0.02 0.080.10 0.11 SEQID-00808 E7QA23 — 1 0.42 0.19 0.03 0.06 0.08 0.06 0.00 0.050.14 0.02 0.02 0.06 0.09 0.07 SEQID-00809 P02669 — 1 0.41 0.19 0.07 0.040.05 0.04 0.01 0.09 0.07 0.01 0.03 0.06 0.06 0.05 SEQID-00810 E7Q742 — 10.49 0.24 0.03 0.06 0.06 0.07 0.01 0.04 0.09 0.03 0.04 0.07 0.10 0.06SEQID-00811 E7Q4K4 — 1 0.49 0.22 0.04 0.03 0.03 0.08 0.01 0.04 0.08 0.040.03 0.05 0.12 0.07 SEQID-00812 E7Q3Y5 — 1 0.47 0.22 0.02 0.05 0.06 0.090.00 0.04 0.09 0.01 0.02 0.06 0.13 0.07 SEQID-00813 O22493 — 1 0.48 0.200.04 0.08 0.03 0.06 0.01 0.03 0.08 0.05 0.02 0.05 0.09 0.07 SEQID-00814P00698 — 1 0.42 0.20 0.06 0.12 0.10 0.05 0.06 0.02 0.02 0.05 0.01 0.050.10 0.05 SEQID-00815 E7Q1A8 — 1 0.49 0.20 0.03 0.03 0.07 0.08 0.00 0.040.07 0.02 0.03 0.06 0.10 0.10 SEQID-00816 E7Q2C3 — 1 0.50 0.17 0.05 0.060.06 0.07 0.01 0.04 0.09 0.02 0.03 0.08 0.12 0.08 SEQID-00817 E7Q315 — 10.51 0.25 0.02 0.01 0.08 0.08 0.03 0.05 0.04 0.03 0.03 0.09 0.11 0.09SEQID-00818 E7Q0X9 — 1 0.44 0.21 0.03 0.068 0.09 0.07 0.01 0.06 0.070.01 0.02 0.06 0.11 0.09 SEQID-00819 P62796 — 0 0.48 0.22 0.04 0.19 0.020.03 0.00 0.02 0.05 0.09 0.02 0.06 0.08 0.12 SEQID-00820 E7Q903 — 1 0.340.09 0.03 0.07 0.10 0.08 0.00 0.10 0.06 0.05 0.01 0.03 0.04 0.08SEQID-00821 E7QA30 — 1 0.48 0.21 0.04 0.05 0.04 0.07 0.00 0.03 0.15 0.020.01 0.07 0.09 0.12 SEQID-00822 Q69IM0 — 1 0.48 0.24 0.07 0.09 0.02 0.070.01 0.04 0.09 0.05 0.03 0.07 0.08 0.08 SEQID-00823 F6HQQ4 — 1 0.50 0.240.04 0.08 0.04 0.05 0.02 0.05 0.06 0.02 0.04 0.08 0.09 0.07 SEQID-00824F6HHW7 — 1 0.47 0.19 0.04 0.05 0.05 0.05 0.01 0.04 0.07 0.04 0.04 0.050.08 0.08 SEQID-00825 E7Q876 — 1 0.48 0.22 0.02 0.06 0.07 0.07 0.01 0.070.11 0.01 0.02 0.07 0.11 0.13 SEQID-00826 E7Q4C4 — 1 0.42 0.16 0.03 0.040.08 0.08 0.00 0.07 0.10 0.03 0.03 0.04 0.06 0.08 SEQID-00827 E7Q7F8 — 10.45 0.21 0.04 0.06 0.06 0.06 0.01 0.06 0.06 0.02 0.03 0.07 0.09 0.07SEQID-00828 K9HAR9 — 1 0.45 0.22 0.05 0.09 0.03 0.07 0.01 0.03 0.08 0.050.02 0.06 0.10 0.07 SEQID-00829 F1MPS8 — 1 0.44 0.19 0.03 0.08 0.04 0.050.01 0.10 0.14 0.02 0.03 0.04 0.11 0.12 SEQID-00830 K7K247 — 1 0.43 0.120.04 0.04 0.05 0.04 0.01 0.07 0.15 0.01 0.03 0.03 0.07 0.19 SEQID-00831K9HJK7 — 1 0.47 0.22 0.05 0.09 0.03 0.06 0.01 0.04 0.08 0.03 0.03 0.060.10 0.05 SEQID-00832 K9HV52 — 1 0.42 0.19 0.05 0.11 0.04 0.04 0.03 0.030.10 0.05 0.03 0.05 0.10 0.04 SEQID-00833 E1C4H7 — 1 0.44 0.22 0.05 0.070.03 0.05 0.02 0.06 0.08 0.04 0.04 0.04 0.12 0.05 SEQID-00834 E1BTL7 — 10.42 0.19 0.03 0.09 0.05 0.05 0.02 0.08 0.06 0.02 0.02 0.05 0.06 0.07SEQID-00835 I1N1P3 — 1 0.48 0.21 0.05 0.08 0.04 0.05 0.02 0.05 0.08 0.030.04 0.05 0.09 0.11 SEQID-00836 W5PEW5 — 1 0.42 0.20 0.03 0.06 0.04 0.040.01 0.10 0.18 0.01 0.02 0.03 0.13 0.11 SEQID-00837 B0JEU3 — 1 0.35 0.160.03 0.12 0.06 0.04 0.02 0.13 0.11 0.04 0.02 0.04 0.07 0.06 SEQID-00838P00724 — 1 0.45 0.16 0.04 0.03 0.08 0.06 0.00 0.04 0.06 0.03 0.01 0.040.07 0.05 SEQID-00839 P00724 — 1 0.45 0.16 0.04 0.03 0.08 0.06 0.00 0.040.06 0.03 0.01 0.04 0.07 0.05 SEQID-00840 K9HWU9 — 1 0.43 0.20 0.07 0.070.05 0.07 0.01 0.03 0.06 0.05 0.02 0.06 0.07 0.04 SEQID-00841 Q653V7 — 10.45 0.21 0.06 0.10 0.04 0.06 0.00 0.02 0.03 0.06 0.03 0.03 0.10 0.03SEQID-00842 K9HXA6 — 1 0.46 0.17 0.05 0.06 0.05 0.05 0.01 0.07 0.05 0.050.03 0.05 0.07 0.04 SEQID-00843 P23776 — 1 0.43 0.19 0.04 0.05 0.06 0.090.02 0.05 0.07 0.03 0.03 0.06 0.09 0.04 SEQID-00844 F1MM32 — 1 0.46 0.200.06 0.10 0.03 0.06 0.02 0.04 0.06 0.04 0.03 0.06 0.10 0.05 SEQID-00845P80025 — 1 0.46 0.20 0.04 0.09 0.06 0.05 0.02 0.05 0.06 0.06 0.03 0.040.11 0.06 SEQID-00846 Q67UF5 — 1 0.46 0.21 0.08 0.03 0.04 0.05 0.02 0.040.10 0.04 0.01 0.03 0.10 0.11 SEQID-00847 Q95114 — 1 0.45 0.18 0.04 0.070.06 0.05 0.04 0.06 0.05 0.05 0.03 0.05 0.09 0.04 SEQID-00848 F1MGU7 — 10.44 0.17 0.03 0.04 0.06 0.07 0.02 0.06 0.06 0.04 0.03 0.06 0.07 0.08SEQID-00849 P15703 — 1 0.46 0.17 0.06 0.02 0.05 0.08 0.01 0.05 0.06 0.040.01 0.04 0.06 0.06 SEQID-00850 P53334 — 1 0.39 0.18 0.10 0.02 0.06 0.060.01 0.05 0.05 0.03 0.01 0.05 0.05 0.06 SEQID-00851 B4FBD6 — 1 0.38 0.170.07 0.07 0.04 0.08 0.04 0.05 0.04 0.05 0.02 0.02 0.10 0.04 SEQID-00852E0CQY0 — 1 0.45 0.16 0.06 0.05 0.07 0.04 0.09 0.06 0.01 0.06 0.02 0.040.05 0.05 SEQID-00853 P01888 — 1 0.45 0.22 0.02 0.07 0.03 0.07 0.02 0.060.06 0.02 0.04 0.05 0.12 0.08 SEQID-00854 F1SU23 — 1 0.39 0.16 0.05 0.110.03 0.09 0.01 0.06 0.05 0.03 0.03 0.01 0.11 0.06 SEQID-00855 Q3SZR3 — 10.47 0.19 0.06 0.05 0.04 0.05 0.02 0.04 0.11 0.02 0.03 0.06 0.09 0.09SEQID-00856 Q9MZ06 — 1 0.47 0.18 0.03 0.08 0.05 0.04 0.04 0.05 0.09 0.030.02 0.03 0.10 0.11 SEQID-00857 Q3ZCH5 — 1 0.38 0.15 0.06 0.09 0.02 0.050.01 0.06 0.10 0.04 0.03 0.02 0.09 0.04 SEQID-00858 G1MZ49 — 0 0.48 0.250.04 0.07 0.07 0.06 0.02 0.03 0.07 0.02 0.02 0.07 0.14 0.07 SEQID-00859P80195 — 0 0.50 0.23 0.04 0.05 0.05 0.03 0.01 0.05 0.12 0.01 0.04 0.070.14 0.10 SEQID-00860 P04272 — 1 0.45 0.21 0.04 0.08 0.03 0.09 0.01 0.040.08 0.03 0.01 0.06 0.10 0.11 SEQID-00861 P60712 — 1 0.47 0.20 0.05 0.070.02 0.06 0.01 0.04 0.08 0.04 0.03 0.08 0.07 0.06 SEQID-00862 P63258 — 10.47 0.20 0.05 0.07 0.02 0.06 0.01 0.04 0.09 0.04 0.03 0.08 0.07 0.06SEQID-00863 I1M076 — 0 0.52 0.26 0.02 0.07 0.03 0.08 0.00 0.09 0.08 0.040.02 0.09 0.12 0.11 SEQID-00864 P27161 — 0 0.45 0.17 0.05 0.05 0.04 0.110.01 0.05 0.17 0.03 0.01 0.05 0.08 0.08 SEQID-00865 Q84MN0 — 0 0.45 0.190.03 0.05 0.05 0.11 0.01 0.05 0.16 0.04 0.00 0.05 0.09 0.06 SEQID-00866Q948R0 — 0 0.40 0.19 0.05 0.10 0.02 0.12 0.01 0.05 0.16 0.05 0.01 0.040.08 0.03 SEQID-00867 O23320 — 0 0.47 0.21 0.04 0.01 0.05 0.11 0.01 0.050.17 0.02 0.02 0.08 0.09 0.08 SEQID-00868 Q95744 — 0 0.48 0.16 0.05 0.030.02 0.11 0.01 0.06 0.11 0.04 0.02 0.07 0.07 0.08 SEQID-00869 Q41420 — 00.46 0.19 0.04 0.06 0.06 0.11 0.01 0.03 0.15 0.03 0.01 0.06 0.07 0.07SEQID-00870 Q2R1Z5 — 1 0.45 0.16 0.03 0.06 0.06 0.12 0.01 0.03 0.13 0.020.01 0.06 0.06 0.07 SEQID-00871 Q

6A5 — 0 0.48 0.22 0.03 0.06 0.05 0.08 0.02 0.02 0.11 0.04 0.02 0.07 0.090.11 SEQID-00872 P00571 — 0 0.49 0.22 0.03 0.08 0.01 0.06 0.01 0.04 0.110.05 0.01 0.05 0.09 0.12 SEQID-00873 P05081 — 0 0.50 0.22 0.03 0.07 0.010.06 0.01 0.04 0.11 0.05 0.03 0.05 0.10 0.13 SEQID-00874 A5PJA1 — 1 0.460.24 0.01 0.05 0.06 0.08 0.02 0.04 0.12 0.03 0.04 0.07 0.11 0.08SEQID-00875 Q9TTU2 — 1 0.45 0.22 0.01 0.07 0.05 0.07 0.02 0.04 0.14 0.030.03 0.07 0.10 0.06 SEQID-00876 Q9UU88 — 1 0.49 0.23 0.01 0.05 0.05 0.060.03 0.03 0.17 0.03 0.03 0.08 0.10 0.08 SEQID-00877 Q12055 — 1 0.40 0.200.02 0.07 0.06 0.12 0.02 0.03 0.11 0.03 0.04 0.05 0.07 0.07 SEQID-00878Q2KIW9 — 1 0.44 0.20 0.03 0.03 0.05 0.08 0.02 0.05 0.10 0.04 0.01 0.070.07 0.11 SEQID-00879 Q5ZKE7 — 1 0.43 0.20 0.03 0.11 0.04 0.08 0.02 0.040.09 0.05 0.01 0.07 0.07 0.09 SEQID-00880 P54877 — 0 0.28 0.09 0.10 0.100.02 0.12 0.04 0.02 0.03 0.14 0.02 0.06 0.03 0.10 SEQID-00881 Q10980 — 00.21 0.01 0.07 0.13 0.03 0.07 0.21 0.02 0.03 0.10 0.03 0.00 0.00 0.02SEQID-00882 Q08000 — 0 0.28 0.09 0.04 0.16 0.02 0.05 0.00 0.06 0.18 0.100.01 0.02 0.05 0.08 SEQID-00883 Q6H595 — 1 0.31 0.09 0.11 0.16 0.02 0.090.08 0.05 0.05 0.07 0.03 0.01 0.04 0.08 SEQID-00884 Q6Z461 — 0 0.26 0.100.12 0.17 0.03 0.05 0.03 0.05 0.05 0.07 0.04 0.01 0.05 0.05 SEQID-00885Q3T0I4 — 1 0.31 0.13 0.07 0.19 0.04 0.08 0.00 0.07 0.03 0.11 0.02 0.030.07 0.05 SEQID-00886 P46202  96:211 1 0.60 0.23 0.03 0.07 0.06 0.100.01 0.06 0.06 0.00 0.05 0.07 0.11 0.17 SEQID-00887 Q03336 281:356 10.48 0.16 0.02 0.12 0.09 0.06 0.01 0.06 0.11 0.00 0.04 0.04 0.05 0.15SEQID-00888 P40568 331:406 1 0.37 0.17 0.02 0.03 0.04 0.26 0.00 0.030.18 0.00 0.01 0.06 0.06 0.08 SEQID-00889 Q32LH1  21:116 1 0.38 0.170.04 0.12 0.01 0.01 0.00 0.14 0.26 0.00 0.01 0.03 0.12 0.06 SEQID-00890Q29RL0 676:821 1 0.33 0.17 0.04 0.21 0.01 0.07 0.00 0.13 0.17 0.00 0.020.04 0.09 0.05 SEQID-00891 Q2TBK0  56:181 1 0.40 0.14 0.07 0.11 0.020.03 0.01 0.13 0.21 0.00 0.04 0.04 0.07 0.10 SEQID-00892 Q06698 146:2261 0.47 0.16 0.04 0.11 0.08 0.08 0.00 0.08 0.07 0.00 0.03 0.03 0.09 0.13SEQID-00893 P53061 251:321 1 0.56 0.18 0.01 0.06 0.06 0.08 0.02 0.040.10 0.00 0.02 0.05 0.10 0.22 SEQID-00894 Q9BE40 — — 1 0.45 0.19 0.050.07 0.04 0.05 0.01 0.07 0.15 0.02 0.02 0.05 0.10 0.12 SEQID-00895F1MRC2 — — 1 0.45 0.19 0.05 0.07 0.04 0.05 0.01 0.07 0.15 0.02 0.02 0.050.10 0.12 SEQID-00896 F1N757 — — 1 0.47 0.21 0.04 0.06 0.03 0.05 0.020.05 0.11 0.03 0.02 0.06 0.07 0.09 SEQID-00897 Q9BE39 — — 1 0.45 0.190.05 0.08 0.05 0.05 0.01 0.07 0.15 0.02 0.02 0.05 0.11 0.12 SEQID-00898P68138 — — 1 0.47 0.20 0.05 0.07 0.03 0.06 0.01 0.03 0.09 0.04 0.03 0.080.07 0.06 SEQID-00899 P63258 — — 1 0.47 0.20 0.05 0.07 0.02 0.06 0.010.04 0.09 0.04 0.03 0.08 0.07 0.06 SEQID-00900 F1MZX6 — — 1 0.44 0.190.05 0.07 0.05 0.05 0.01 0.08 0.14 0.02 0.02 0.04 0.11 0.11 SEQID-00901Q9XSC6 — — 1 0.50 0.20 0.03 0.07 0.05 0.07 0.01 0.04 0.03 0.04 0.05 0.040.10 0.10 SEQID-00902 F1MJ28 — — 1 0.46 0.21 0.05 0.10 0.05 0.06 0.010.04 0.09 0.03 0.03 0.06 0.09 0.07 SEQID-00903 Q3ZCS5 — — 1 0.44 0.200.05 0.09 0.05 0.06 0.01 0.07 0.11 0.02 0.03 0.07 0.09 0.07 SEQID-00904Q0III9 — — 1 0.43 0.20 0.06 0.10 0.04 0.06 0.01 0.07 0.11 0.03 0.03 0.050.10 0.06 SEQID-00905 Q5KR49 — — 0 0.40 0.18 0.08 0.07 0.02 0.08 0.000.05 0.22 0.00 0.01 0.04 0.11 0.15 SEQID-00906 Q3ZC09 — — 1 0.47 0.220.07 0.06 0.05 0.06 0.01 0.03 0.08 0.05 0.02 0.06 0.09 0.10 SEQID-00907A6QP89 — — 1 0.46 0.19 0.05 0.06 0.04 0.07 0.01 0.03 0.11 0.03 0.02 0.070.06 0.11 SEQID-00908 Q5KR48 — — 0 0.39 0.17 0.07 0.07 0.02 0.08 0.010.06 0.23 0.01 0.00 0.04 0.10 0.15 SEQID-00909 P10096 — — 1 0.52 0.220.06 0.04 0.06 0.06 0.01 0.02 0.05 0.05 0.04 0.07 0.06 0.09 SEQID-00910P19858 — — 1 0.53 0.28 0.04 0.05 0.05 0.05 0.02 0.04 0.06 0.04 0.03 0.080.11 0.09 SEQID-00911 E1BF23 — — 1 0.45 0.20 0.04 0.08 0.03 0.06 0.020.04 0.09 0.03 0.04 0.04 0.08 0.08 SEQID-00912 A0JNJ5 — — 0 0.44 0.170.08 0.03 0.06 0.05 0.01 0.05 0.14 0.03 0.01 0.04 0.08 0.12 SEQID-00913P02769 — — 1 0.46 0.19 0.05 0.06 0.02 0.07 0.05 0.04 0.11 0.01 0.03 0.030.11 0.11 SEQID-00914 Q0VCY0 — — 1 0.49 0.25 0.06 0.07 0.04 0.05 0.020.03 0.09 0.04 0.02 0.07 0.10 0.06 SEQID-00915 A5D984 — — 1 0.48 0.230.07 0.08 0.04 0.06 0.02 0.03 0.08 0.04 0.03 0.08 0.08 0.08 SEQID-00916Q0BDP0 — — 1 0.48 0.23 0.05 0.06 0.04 0.06 0.01 0.04 0.06 0.05 0.02 0.090.08 0.08 SEQID-00917 F1MR86 — — 1 0.46 0.12 0.04 0.04 0.04 0.05 0.100.05 0.04 0.03 0.06 0.02 0.03 0.14 SEQID-00918 Q3SZX4 — — 1 0.47 0.170.05 0.06 0.05 0.05 0.02 0.02 0.07 0.03 0.06 0.04 0.09 0.09 SEQID-00919Q0IIG5 — — 1 0.48 0.22 0.05 0.10 0.04 0.05 0.02 0.03 0.07 0.05 0.03 0.060.08 0.06 SEQID-00920 F1MQI3 — — 1 0.47 0.17 0.04 0.06 0.04 0.08 0.010.05 0.07 0.02 0.04 0.05 0.07 0.13 SEQID-00921 Q3ZBD7 — — 1 0.51 0.200.04 0.06 0.05 0.04 0.01 0.05 0.07 0.04 0.04 0.06 0.09 0.07 SEQID-00922G3MYN5 — — 1 0.47 0.20 0.05 0.14 0.02 0.06 0.01 0.03 0.12 0.02 0.03 0.020.12 0.15 SEQID-00923 E1BNV1 — — 1 0.47 0.20 0.04 0.07 0.03 0.06 0.010.04 0.10 0.03 0.02 0.05 0.07 0.11 SEQID-00924 E1BE25 — — 1 0.44 0.200.05 0.06 0.03 0.06 0.02 0.03 0.08 0.06 0.03 0.05 0.05 0.07 SEQID-00925F1MV90 — — 1 0.40 0.19 0.07 0.10 0.02 0.05 0.02 0.08 0.21 0.01 0.01 0.050.11 0.12 SEQID-00926 Q3TDP6 — — 1 0.52 0.23 0.06 0.04 0.05 0.06 0.020.02 0.07 0.05 0.02 0.05 0.10 0.12 SEQID-00927 Q0P571 — — 1 0.48 0.160.06 0.05 0.05 0.09 0.01 0.05 0.10 0.04 0.01 0.06 0.05 0.11 SEQID-00928A5PJM2 — — 1 0.41 0.15 0.04 0.15 0.02 0.06 0.02 0.05 0.14 0.02 0.04 0.020.09 0.12 SEQID-00929 Q5E956 — — 1 0.48 0.22 0.08 0.05 0.05 0.05 0.020.05 0.08 0.05 0.02 0.06 0.07 0.10 SEQID-00930 P02510 — — 1 0.48 0.190.03 0.11 0.01 0.06 0.00 0.02 0.09 0.02 0.06 0.06 0.08 0.06 SEQID-00931Q8MKI3 — — 1 0.37 0.13 0.05 0.13 0.02 0.06 0.00 0.06 0.21 0.01 0.03 0.030.07 0.15 SEQID-00932 Q3ZBP1 — — 1 0.45 0.21 0.04 0.11 0.04 0.07 0.020.04 0.07 0.04 0.03 0.05 0.10 0.07 SEQID-00933 O62654 — — 1 0.37 0.190.06 0.13 0.04 0.05 0.00 0.08 0.14 0.02 0.02 0.04 0.10 0.05 SEQID-00934F1MPR3 — — 1 0.50 0.24 0.05 0.06 0.04 0.05 0.03 0.03 0.09 0.03 0.01 0.070.09 0.07 SEQID-00935 P00929 — — 0 0.45 0.26 0.08 0.07 0.02 0.06 0.000.06 0.08 0.05 0.02 0.07 0.10 0.05 SEQID-00936 Q32KV0 — — 1 0.48 0.180.06 0.09 0.03 0.05 0.01 0.04 0.10 0.03 0.03 0.06 0.08 0.10 SEQID-00937F1MHT1 — — 1 0.45 0.21 0.04 0.08 0.05 0.05 0.02 0.04 0.07 0.03 0.04 0.050.10 0.06 SEQID-00938 Q04467 — — 1 0.50 0.19 0.05 0.07 0.04 0.07 0.020.05 0.06 0.04 0.04 0.06 0.07 0.09 SEQID-00939 P19483 — — 0 0.44 0.250.07 0.10 0.03 0.06 0.00 0.05 0.07 0.05 0.01 0.08 0.10 0.07 SEQID-00940E18B91 — — 1 0.42 0.23 0.05 0.09 0.04 0.06 0.01 0.06 0.07 0.05 0.01 0.050.10 0.06 SEQID-00941 P85100 — — 0 0.46 0.15 0.06 0.04 0.03 0.06 0.010.04 0.14 0.04 0.02 0.04 0.07 0.12 SEQID-00942 Q14BH2 — — 0 0.44 0.220.04 0.07 0.02 0.06 0.01 0.04 0.12 0.03 0.02 0.04 0.10 0.10 SEQID-00943F1MME6 — — 1 0.44 0.19 0.05 0.07 0.03 0.05 0.01 0.04 0.10 0.03 0.03 0.050.06 0.09 SEQID-00944 Q3SZE5 — — 0 0.50 0.16 0.05 0.04 0.06 0.08 0.000.05 0.12 0.03 0.01 0.06 0.06 0.11 SEQID-00945 P00570 — — 0 0.48 0.220.03 0.09 0.02 0.05 0.01 0.04 0.11 0.05 0.01 0.05 0.09 0.11 SEQID-00946Q3T149 — — 1 0.40 0.17 0.05 0.10 0.02 0.04 0.00 0.06 0.10 0.04 0.03 0.030.09 0.04 SEQID-00947 Q5EA88 — — 1 0.52 0.25 0.05 0.04 0.05 0.04 0.030.05 0.08 0.05 0.04 0.08 0.09 0.09 SEQID-00948 Q32LG3 — — 0 0.50 0.250.08 0.05 0.04 0.04 0.02 0.03 0.07 0.04 0.02 0.07 0.10 0.09 SEQID-00949Q27965 — — 1 0.45 0.21 0.06 0.08 0.05 0.07 0.01 0.05 0.09 0.04 0.02 0.070.08 0.09 SEQID-00950 P02070 — — 0 0.57 0.23 0.07 0.04 0.05 0.06 0.010.02 0.06 0.04 0.05 0.00 0.12 0.10 SEQID-00951 P12344 — — 1 0.47 0.190.07 0.07 0.04 0.05 0.02 0.05 0.06 0.04 0.03 0.06 0.08 0.08 SEQID-00952A4FV78 — — 1 0.47 0.24 0.04 0.05 0.04 0.08 0.02 0.04 0.09 0.03 0.01 0.060.11 0.10 SEQID-00953 F1MJW7 — — 1 0.35 0.17 0.06 0.07 0.03 0.06 0.010.04 0.16 0.05 0.03 0.04 0.09 0.05 SEQID-00954 E1BF59 — — 1 0.37 0.200.07 0.13 0.01 0.04 0.01 0.09 0.14 0.03 0.02 0.03 0.12 0.06 SEQID-00955P01966 — — 0 0.56 0.23 0.09 0.03 0.02 0.06 0.00 0.01 0.04 0.03 0.09 0.000.15 0.09 SEQID-00956 Q8SQ24 — — 1 0.41 0.16 0.03 0.06 0.04 0.04 0.000.06 0.07 0.08 0.03 0.04 0.09 0.08 SEQID-00957 Q5E9B1 — — 1 0.53 0.290.04 0.04 0.05 0.05 0.01 0.04 0.08 0.04 0.03 0.03 0.11 0.09 SEQID-00958P33097 — — 1 0.46 0.20 0.05 0.03 0.05 0.05 0.01 0.04 0.07 0.03 0.02 0.050.09 0.06 SEQID-00959 P19120 — — 1 0.46 0.20 0.05 0.06 0.05 0.07 0.010.05 0.09 0.04 0.01 0.07 0.07 0.10 SEQID-00960 Q148F8 — — 1 0.37 0.220.11 0.10 0.00 0.04 0.01 0.04 0.09 0.03 0.05 0.03 0.11 0.02 SEQID-00961Q8MKH6-2 — — 1 0.38 0.14 0.04 0.14 0.02 0.04 0.00 0.06 0.22 0.02 0.030.04 0.07 0.14 SEQID-00962 F1MPU4 — — 1 0.33 0.16 0.05 0.08 0.06 0.040.01 0.09 0.06 0.02 0.02 0.04 0.07 0.07 SEQID-00963 F1MLX6 — — 1 0.480.18 0.03 0.06 0.06 0.05 0.01 0.04 0.07 0.02 0.04 0.04 0.09 0.09SEQID-00964 G3N3C9 — — 1 0.37 0.14 0.07 0.06 0.03 0.04 0.03 0.06 0.050.03 0.03 0.04 0.06 0.06 SEQID-00965 Q9N0V4 — — 1 0.50 0.22 0.09 0.080.04 0.07 0.01 0.02 0.08 0.03 0.02 0.06 0.12 0.09 SEQID-00966 P02722 — —1 0.51 0.21 0.07 0.08 0.03 0.05 0.01 0.05 0.02 0.05 0.01 0.07 0.08 0.09SEQID-00967 Q3T145 — — 1 0.51 0.25 0.06 0.04 0.04 0.08 0.01 0.03 0.060.04 0.02 0.07 0.10 0.11 SEQID-00968 P68252 — — 1 0.39 0.19 0.06 0.070.06 0.07 0.01 0.05 0.13 0.02 0.02 0.04 0.10 0.08 SEQID-00969 P45879 — —1 0.50 0.19 0.05 0.04 0.07 0.05 0.01 0.03 0.06 0.06 0.01 0.04 0.10 0.10SEQID-00970 P81948 — — 1 0.44 0.20 0.05 0.07 0.04 0.07 0.03 0.04 0.090.04 0.04 0.06 0.07 0.05 SEQID-00971 E1BI98 — — 1 0.37 0.18 0.05 0.090.03 0.08 0.02 0.05 0.08 0.08 0.02 0.04 0.07 0.07 SEQID-00972 PG8432 — —0 0.43 0.18 0.08 0.18 0.01 0.03 0.01 0.07 0.06 0.03 0.02 0.05 0.09 0.11SEQID-00973 Q5E946 — — 0 0.49 0.26 0.07 0.05 0.02 0.06 0.02 0.03 0.100.05 0.02 0.06 0.10 0.12 SEQID-00974 Q77834 — — 1 0.50 0.22 0.05 0.070.04 0.07 0.00 0.02 0.08 0.03 0.02 0.07 0.10 0.10 SEQID-00975 P62261 — —1 0.41 0.20 0.06 0.07 0.04 0.09 0.01 0.04 0.13 0.02 0.01 0.05 0.10 0.08SEQID-00976 Q2KHU5 — — 1 0.44 0.20 0.08 0.11 0.02 0.04 0.03 0.03 0.070.04 0.03 0.04 0.11 0.08 SEQID-00977 P31800 — — 1 0.41 0.20 0.07 0.090.04 0.05 0.03 0.05 0.07 0.04 0.04 0.04 0.11 0.03 SEQID-00978 E1BE77 — —1 0.41 0.20 0.06 0.11 0.02 0.04 0.03 0.05 0.10 0.04 0.04 0.02 0.13 0.05SEQID-00979 P62803 — — 0 0.48 0.22 0.04 0.19 0.02 0.03 0.00 0.02 0.050.09 0.02 0.06 0.08 0.12 SEQID-00980 G3MZK7 — — 0 0.45 0.15 0.05 0.070.00 0.11 0.01 0.04 0.18 0.04 0.00 0.06 0.06 0.06 SEQID-00981 A1A4R1 — —0 0.44 0.23 0.09 0.13 0.05 0.02 0.00 0.05 0.06 0.05 0.03 0.05 0.12 0.13SEQID-00982 P62808 — — 0 0.48 0.16 0.07 0.09 0.02 0.02 0.00 0.03 0.060.03 0.03 0.05 0.05 0.18 SEQID-00983 Q5E947 — — 1 0.51 0.20 0.04 0.050.03 0.08 0.02 0.06 0.04 0.04 0.02 0.08 0.06 0.11 SEQID-00984 P13621 — —0 0.52 0.26 0.06 0.07 0.03 0.02 0.01 0.04 0.07 0.02 0.01 0.05 0.12 0.11SEQID-00985 P28801 — — 1 0.43 0.23 0.05 0.06 0.04 0.06 0.02 0.09 0.050.04 0.02 0.03 0.14 0.07 SEQID-00986 Q3SYR3 — — 1 0.42 0.17 0.06 0.070.04 0.03 0.02 0.05 0.16 0.02 0.02 0.04 0.09 0.07 SEQID-00987 Q3ZBU0 — —1 0.46 0.17 0.04 0.09 0.04 0.05 0.01 0.06 0.06 0.04 0.05 0.05 0.07 0.10SEQID-00988 P13272 — — 1 0.43 0.22 0.07 0.10 0.02 0.05 0.02 0.03 0.060.03 0.03 0.04 0.08 0.07 SEQID-00989 Q3Z8I6 — — 1 0.34 0.10 0.03 0.080.01 0.06 0.12 0.07 0.07 0.05 0.04 0.01 0.06 0.04 SEQID-00990 Q3SYZ8 — —1 0.38 0.17 0.07 0.10 0.05 0.06 0.02 0.06 0.06 0.04 0.04 0.05 0.07 0.06SEQID-00991 P04272 — — 1 0.45 0.21 0.04 0.08 0.03 0.09 0.01 0.04 0.080.03 0.01 0.06 0.10 0.11 SEQID-00992 P23004 — — 1 0.43 0.22 0.09 0.060.05 0.04 0.00 0.05 0.06 0.04 0.04 0.04 0.11 0.06 SEQID-00993 P11179 — —1 0.44 0.22 0.08 0.10 0.03 0.05 0.01 0.03 0.07 0.03 0.01 0.06 0.07 0.07SEQID-00994 Q32PH8 — — 1 0.50 0.22 0.05 0.06 0.04 0.05 0.01 0.03 0.080.05 0.03 0.08 0.06 0.12 SEQID-00995 Q29RK1 — — 1 0.48 0.22 0.06 0.060.04 0.05 0.01 0.05 0.06 0.04 0.03 0.04 0.13 0.06 SEQID-00996 F1N690 — —1 0.44 0.21 0.08 0.07 0.03 0.04 0.01 0.04 0.07 0.04 0.01 0.07 0.07 0.07SEQID-00997 P79134 — — 1 0.45 0.20 0.06 0.09 0.02 0.08 0.01 0.04 0.100.03 0.02 0.07 0.10 0.09 SEQID-00998 P20004 — — 1 0.47 0.22 0.05 0.070.05 0.06 0.02 0.04 0.06 0.05 0.04 0.08 0.09 0.08 SEQID-00999 Q76LV2 — —1 0.47 0.19 0.03 0.06 0.04 0.07 0.01 0.04 0.15 0.02 0.02 0.07 0.08 0.12SEQID-01000 E1BCU2 — — 1 0.42 0.19 0.04 0.10 0.03 0.06 0.01 0.05 0.100.03 0.02 0.04 0.08 0.07 SEQID-01001 P02789 — — 1 0.45 0.18 0.05 0.060.04 0.07 0.04 0.04 0.07 0.04 0.02 0.04 0.08 0.10 SEQID-01002 E1BQC2 — —1 0.46 0.19 0.05 0.06 0.04 0.07 0.04 0.03 0.07 0.04 0.02 0.04 0.08 0.09SEQID-01003 F1NZY2 — — 1 0.42 0.17 0.03 0.04 0.05 0.06 0.09 0.04 0.070.03 0.03 0.05 0.05 0.07 SEQID-01004 P01014 — — 1 0.52 0.21 0.04 0.040.06 0.04 0.01 0.01 0.10 0.03 0.02 0.06 0.09 0.07 SEQID-01005 P00698 — —1 0.42 0.20 0.06 0.12 0.10 0.05 0.06 0.02 0.02 0.05 0.01 0.05 0.10 0.05SEQID-01006 P01005 — — 0 0.41 0.16 0.05 0.04 0.07 0.09 0.09 0.01 0.070.05 0.02 0.02 0.07 0.07 SEQID-01007 F1NFY4 — — 1 0.39 0.17 0.04 0.080.05 0.06 0.09 0.03 0.07 0.04 0.04 0.05 0.06 0.06 SEQID-01008 E1C546 — —1 0.49 0.23 0.04 0.05 0.05 0.05 0.02 0.06 0.07 0.02 0.02 0.07 0.09 0.07SEQID-01009 F1NIV0 — — 1 0.49 0.22 0.05 0.05 0.03 0.03 0.02 0.06 0.060.03 0.03 0.04 0.10 0.06 SEQID-01010 P01013 — — 1 0.54 0.22 0.04 0.040.05 0.05 0.00 0.03 0.10 0.02 0.03 0.06 0.10 0.03 SEQID-01011 E1BTF4 — —1 0.53 0.24 0.05 0.05 0.05 0.05 0.01 0.03 0.08 0.02 0.02 0.05 0.13 0.10SEQID-01012 F1N8Q8 — — 1 0.43 0.18 0.03 0.12 0.03 0.06 0.02 0.07 0.110.03 0.03 0.03 0.11 0.04 SEQID-01013 E1C1X2 — — 1 0.49 0.28 0.06 0.060.02 0.04 0.03 0.05 0.05 0.03 0.04 0.02 0.16 0.04 SEQID-01014 F1P2P7 — —0 0.49 0.18 0.06 0.04 0.04 0.05 0.02 0.04 0.14 0.03 0.08 0.04 0.09 0.08SEQID-01015 O42273 — — 1 0.50 0.29 0.07 0.06 0.01 0.05 0.02 0.05 0.060.02 0.03 0.04 0.16 0.04 SEQID-01016 F1NTK2 — — 1 0.52 0.22 0.03 0.050.03 0.04 0.02 0.06 0.06 0.03 0.03 0.06 0.09 0.07 SEQID-01017 F1NBL0 — —1 0.42 0.17 0.03 0.05 0.06 0.05 0.08 0.04 0.07 0.03 0.02 0.06 0.06 0.07SEQID-01018 P02701 — — 1 0.56 0.22 0.03 0.07 0.07 0.03 0.01 0.03 0.050.04 0.02 0.05 0.11 0.07 SEQID-01019 P02752 — — 1 0.39 0.12 0.04 0.050.04 0.05 0.07 0.05 0.11 0.01 0.04 0.04 0.06 0.07 SEQID-01020 P21760 — —1 0.46 0.19 0.07 0.10 0.01 0.06 0.02 0.01 0.12 0.02 0.01 0.02 0.10 0.08SEQID-01021 F1NVN3 — — 1 0.42 0.18 0.06 0.06 0.06 0.05 0.04 0.06 0.060.04 0.02 0.04 0.08 0.06 SEQID-01022 F1N9M9 — — 1 0.57 0.21 0.03 0.020.02 0.00 0.09 0.02 0.00 0.03 0.02 0.05 0.13 0.11 SEQID-01023 F1NPJ8 — —1 0.43 0.21 0.04 0.06 0.06 0.04 0.02 0.06 0.06 0.05 0.01 0.04 0.10 0.07SEQID-01024 P01038 — — 1 0.42 0.24 0.06 0.09 0.03 0.05 0.09 0.06 0.080.03 0.01 0.04 0.11 0.06 SEQID-01025 P41366 — — 1 0.43 0.20 0.04 0.090.04 0.06 0.04 0.04 0.04 0.06 0.01 0.04 0.10 0.06 SEQID-01026 P02668 — —1 0.44 0.20 0.05 0.04 0.04 0.02 0.01 0.09 0.07 0.01 0.02 0.07 0.07 0.06SEQID-01027 P02663 — — 1 0.47 0.18 0.03 0.04 0.06 0.02 0.01 0.08 0.120.00 0.02 0.05 0.07 0.12 SEQID-01028 G5E5H7 — — 1 0.50 0.26 0.06 0.020.03 0.06 0.04 0.06 0.10 0.01 0.01 0.06 0.15 0.10 SEQID-01029 P24627 — —1 0.44 0.19 0.06 0.07 0.04 0.05 0.05 0.05 0.07 0.04 0.02 0.02 0.11 0.09SEQID-01030 F1MUT3 — — 1 0.48 0.20 0.05 0.06 0.04 0.04 0.09 0.04 0.080.04 0.03 0.05 0.09 0.08 SEQID-01031 Q2UVX4 — — 1 0.47 0.23 0.04 0.070.04 0.06 0.01 0.06 0.08 0.03 0.02 0.06 0.09 0.08 SEQID-01032 Q95114 — —1 0.45 0.18 0.04 0.07 0.06 0.05 0.04 0.06 0.05 0.05 0.03 0.05 0.09 0.04SEQID-01033 P18892 — — 1 0.45 0.21 0.04 0.09 0.02 0.05 0.02 0.03 0.110.03 0.02 0.05 0.09 0.05 SEQID-01034 P81265 — — 1 0.42 0.19 0.05 0.070.04 0.06 0.03 0.05 0.07 0.04 0.02 0.04 0.07 0.07 SEQID-01035 P80025 — —1 0.46 0.20 0.04 0.09 0.06 0.05 0.02 0.05 0.06 0.03 0.03 0.04 0.11 0.06SEQID-01036 P80195 — — 0 0.50 0.23 0.04 0.05 0.05 0.03 0.01 0.05 0.120.01 0.04 0.07 0.14 0.10 SEQID-01037 Q9TUM6-2 — — 1 0.45 0.23 0.06 0.050.05 0.06 0.01 0.07 0.08 0.03 0.02 0.05 0.11 0.08 SEQID-01038 P11151 — —1 0.48 0.20 0.04 0.06 0.05 0.05 0.02 0.03 0.07 0.04 0.04 0.05 0.09 0.08SEQID-01039 F1N726 — — 1 0.41 0.21 0.03 0.07 0.05 0.06 0.05 0.05 0.070.04 0.02 0.04 0.11 0.03 SEQID-01040 Q29443 — — 1 0.44 0.17 0.05 0.050.06 0.07 0.05 0.03 0.07 0.04 0.03 0.03 0.08 0.11 SEQID-01041 F1MLW7 — —1 0.42 0.19 0.04 0.04 0.03 0.03 0.03 0.04 0.04 0.05 0.01 0.03 0.08 0.05SEQID-01042 G5EST5 — — 1 0.48 0.22 0.03 0.04 0.03 0.05 0.02 0.04 0.070.03 0.02 0.04 0.08 0.05 SEQID-01043 G5E513 — — 1 0.46 0.19 0.04 0.050.03 0.05 0.02 0.04 0.07 0.03 0.02 0.03 0.07 0.06 SEQID-01044 Q3ZCH5 — —1 0.38 0.15 0.06 0.09 0.02 0.05 0.01 0.06 0.10 0.04 0.03 0.02 0.09 0.04SEQID-01045 P26201 — — 1 0.52 0.24 0.03 0.04 0.06 0.04 0.02 0.03 0.060.03 0.02 0.08 0.09 0.08 SEQID-01046 Q0P569 — — 1 0.39 0.18 0.05 0.100.03 0.06 0.00 0.09 0.15 0.02 0.04 0.01 0.12 0.07 SEQID-01047 E1BGX8 — —1 0.41 0.17 0.04 0.12 0.04 0.06 0.03 0.04 0.05 0.05 0.03 0.04 0.09 0.07SEQID-01048 F1MLW8 — — 1 0.44 0.20 0.06 0.03 0.02 0.07 0.03 0.06 0.040.03 0.02 0.03 0.11 0.07 SEQID-01049 G3N0V0 — — 1 0.46 0.18 0.03 0.060.03 0.05 0.03 0.05 0.06 0.03 0.03 0.02 0.05 0.07 SEQID-01050 F1MGU7 — —1 0.44 0.17 0.03 0.04 0.06 0.07 0.02 0.06 0.06 0.04 0.03 0.06 0.07 0.08SEQID-01051 G5E604 — — 0 0.30 0.17 0.06 0.10 0.06 0.04 0.02 0.08 0.020.06 0.00 0.04 0.06 0.00 SEQID-01052 F6R3I5 — — 1 0.44 0.15 0.05 0.040.08 0.04 0.06 0.05 0.04 0.03 0.03 0.03 0.06 0.07 SEQID-01053 Q4GZT4 — —1 0.55 0.26 0.04 0.05 0.05 0.04 0.02 0.03 0.06 0.04 0.02 0.07 0.13 0.07SEQID-01054 F1N647 — — 1 0.45 0.23 0.05 0.07 0.04 0.04 0.02 0.07 0.070.04 0.03 0.04 0.13 0.04 SEQID-01055 G3MXB5 — — 1 0.42 0.22 0.04 0.020.05 0.03 0.05 0.07 0.04 0.04 0.02 0.02 0.12 0.04 SEQID-01056 Q27960 — —1 0.56 0.28 0.04 0.04 0.04 0.03 0.04 0.03 0.06 0.03 0.01 0.09 0.12 0.07SEQID-01057 G3N028 — — 1 0.34 0.16 0.03 0.06 0.04 0.03 0.03 0.07 0.040.07 0.01 0.05 0.06 0.03 SEQID-01058 P10790 — — 1 0.60 0.22 0.02 0.040.04 0.08 0.01 0.04 0.06 0.04 0.02 0.05 0.07 0.11 SEQID-01059 Q3SZR3 — —1 0.47 0.19 0.06 0.05 0.04 0.05 0.02 0.04 0.11 0.02 0.03 0.06 0.09 0.09SEQID-01060 Q9MZ06 — — 1 0.47 0.18 0.03 0.08 0.05 0.04 0.04 0.05 0.090.03 0.02 0.03 0.10 0.11 SEQID-01061 P02702 — — 1 0.41 0.12 0.05 0.080.06 0.04 0.06 0.05 0.06 0.02 0.04 0.03 0.06 0.06 SEQID-01062 A2I7M9 — —1 0.50 0.36 0.04 0.07 0.05 0.05 0.00 0.05 0.09 0.02 0.03 0.06 0.14 0.06SEQID-01063 Q9XSG3 — — 1 0.48 0.19 0.05 0.05 0.04 0.06 0.01 0.05 0.080.04 0.02 0.07 0.07 0.10 SEQID-01064 A6OL27 — — 1 0.42 0.17 0.04 0.080.04 0.05 0.05 0.04 0.06 0.04 0.03 0.03 0.06 0.08 SEQID-01065 F1MM32 — —1 0.46 0.20 0.06 0.10 0.03 0.03 0.02 0.04 0.06 0.04 0.03 0.03 0.10 0.05SEQID-01066 A0JNP2 — — 0 0.51 0.28 0.08 0.06 0.06 0.04 0.04 0.01 0.050.01 0.00 0.05 0.15 0.07 SEQID-01067 P01888 — — 1 0.45 0.22 0.02 0.070.03 0.07 0.02 0.06 0.06 0.02 0.04 0.05 0.12 0.08 SEQID-01068 G3MXD9 — —0 0.47 0.27 0.03 0.06 0.03 0.03 0.02 0.06 0.03 0.04 0.00 0.02 0.14 0.04SEQID-01069 P10152 — — 0 0.44 0.19 0.02 0.12 0.05 0.07 0.04 0.03 0.050.04 0.05 0.07 0.07 0.07 SEQID-01070 Q3SYR8 — — 1 0.42 0.21 0.03 0.090.06 0.08 0.05 0.04 0.07 0.01 0.01 0.06 0.06 0.06 SEQID-01071 Q8SPP7 — —1 0.38 0.20 0.06 0.12 0.04 0.03 0.03 0.07 0.03 0.05 0.04 0.04 0.09 0.02SEQID-01072 P30932 — — 1 0.55 0.26 0.04 0.04 0.03 0.04 0.04 0.04 0.070.04 0.02 0.10 0.10 0.07 SEQID-01073 P08037-2 — — 1 0.42 0.21 0.04 0.090.05 0.05 0.02 0.05 0.04 0.04 0.03 0.05 0.11 0.05 SEQID-01074 P02676 — —1 0.41 0.15 0.02 0.08 0.06 0.07 0.02 0.06 0.07 0.04 0.02 0.04 0.06 0.09SEQID-01075 Q2TBI0 — — 1 0.51 0.27 0.04 0.07 0.05 0.05 0.01 0.04 0.060.03 0.03 0.06 0.14 0.05 SEQID-01076 Q8WML4 — — 1 0.37 0.14 0.08 0.040.03 0.03 0.01 0.04 0.03 0.04 0.04 0.03 0.07 0.02 SEQID-01077 P04776 — —1 0.38 0.17 0.04 0.08 0.08 0.04 0.02 0.11 0.10 0.04 0.02 0.05 0.08 0.06SEQID-01078 Q94LX2 — — 1 0.35 0.17 0.03 0.11 0.07 0.05 0.01 0.09 0.150.02 0.02 0.05 0.09 0.07 SEQID-01079 Q4LER6 — — 1 0.37 0.16 0.03 0.090.06 0.04 0.01 0.09 0.14 0.02 0.04 0.04 0.08 0.08 SEQID-01080 Q9SB11 — —1 0.35 0.17 0.03 0.09 0.06 0.06 0.01 0.10 0.11 0.03 0.03 0.04 0.08 0.05SEQID-01081 K7LZA4 — — 1 0.37 0.17 0.03 0.08 0.06 0.05 0.01 0.10 0.100.04 0.04 0.04 0.08 0.04 SEQID-01082 P11828 — — 1 0.37 0.17 0.04 0.080.08 0.03 0.02 0.12 0.09 0.03 0.02 0.05 0.08 0.04 SEQID-01083 P04347 — —1 0.36 0.17 0.02 0.09 0.06 0.05 0.01 0.10 0.09 0.04 0.04 0.03 0.08 0.04SEQID-01084 I1LB60 — — 1 0.46 0.17 0.03 0.09 0.04 0.05 0.01 0.05 0.120.03 0.04 0.05 0.08 0.08 SEQID-01085 B3TDK6 — — 1 0.47 0.22 0.04 0.070.05 0.06 0.01 0.03 0.07 0.04 0.04 0.06 0.11 0.07 SEQID-01086 Q04672 — —1 0.46 0.18 0.03 0.09 0.04 0.04 0.01 0.05 0.12 0.03 0.04 0.05 0.08 0.08SEQID-01087 I1JF86 — — 1 0.48 0.19 0.03 0.08 0.04 0.04 0.01 0.04 0.120.03 0.04 0.05 0.10 0.08 SEQID-01088 P09439 — — 1 0.47 0.23 0.04 0.070.05 0.06 0.01 0.04 0.07 0.04 0.03 0.06 0.10 0.07 SEQID-01089 I1LXD1 — —1 0.51 0.21 0.05 0.06 0.04 0.04 0.03 0.03 0.07 0.05 0.03 0.06 0.06 0.09SEQID-01090 P01070 — — 1 0.47 0.22 0.04 0.07 0.05 0.08 0.02 0.03 0.080.04 0.02 0.08 0.09 0.07 SEQID-01091 P08170 — — 1 0.47 0.22 0.04 0.060.05 0.06 0.00 0.04 0.08 0.06 0.04 0.06 0.10 0.07 SEQID-01092 Q2I0H4 — —1 0.53 0.24 0.05 0.05 0.04 0.08 0.01 0.01 0.06 0.05 0.03 0.07 0.07 0.10SEQID-01093 C6T9Z5 — — 1 0.48 0.22 0.06 0.06 0.05 0.06 0.01 0.04 0.080.04 0.05 0.06 0.09 0.08 SEQID-01094 C6TN36 — — 1 0.52 0.24 0.05 0.050.05 0.08 0.01 0.01 0.06 0.04 0.02 0.07 0.06 0.10 SEQID-01095 K7Kl44 — —1 0.55 0.23 0.05 0.04 0.04 0.07 0.00 0.01 0.05 0.04 0.04 0.06 0.08 0.09SEQID-01096 I1KC70 — — 1 0.53 0.24 0.06 0.05 0.04 0.08 0.01 0.01 0.060.05 0.03 0.07 0.06 0.10 SEQID-01097 I1NGF4 — — 0 0.41 0.22 0.03 0.100.07 0.05 0.00 0.08 0.09 0.02 0.02 0.06 0.11 0.05 SEQID-01098 I1N5S0 — —1 0.48 0.22 0.06 0.06 0.05 0.06 0.01 0.04 0.08 0.04 0.05 0.06 0.09 0.03SEQID-01099 I1N747 — — 1 0.46 0.22 0.12 0.09 0.01 0.03 0.00 0.05 0.080.04 0.03 0.03 0.10 0.05 SEQID-01100 P29531 — — 1 0.47 0.23 0.12 0.090.01 0.03 0.00 0.04 0.07 0.04 0.04 0.05 0.09 0.05 SEQID-01101 I1LE33 — —1 0.38 0.17 0.03 0.12 0.05 0.04 0.01 0.07 0.15 0.03 0.04 0.04 0.09 0.07SEQID-01102 I1JH86 — — 1 0.44 0.23 0.08 0.05 0.05 0.02 0.01 0.05 0.090.05 0.03 0.04 0.11 0.08 SEQID-01103 P13917 — — 1 0.47 0.22 0.04 0.050.06 0.03 0.03 0.10 0.02 0.04 0.04 0.04 0.11 0.03 SEQID-01104 I1MAE6 — —1 0.49 0.22 0.06 0.05 0.03 0.05 0.03 0.03 0.08 0.05 0.04 0.06 0.06 0.08SEQID-01105 I1KUG6 — — 1 0.47 0.22 0.05 0.06 0.02 0.06 0.01 0.03 0.090.04 0.03 0.08 0.07 0.06 SEQID-01106 I1MA91 — — 1 0.49 0.21 0.05 0.060.05 0.05 0.03 0.02 0.09 0.05 0.03 0.06 0.07 0.08 SEQID-01107 Q8RVH5 — —1 0.48 0.21 0.04 0.04 0.06 0.03 0.03 0.10 0.02 0.04 0.06 0.04 0.11 0.04SEQID-01108 I1KAJ4 — — 1 0.49 0.22 0.06 0.05 0.04 0.05 0.03 0.02 0.080.06 0.04 0.06 0.06 0.07 SEQID-01109 Q71EW8 — — 1 0.49 0.23 0.06 0.060.04 0.06 0.00 0.03 0.08 0.03 0.02 0.06 0.10 0.08 SEQID-01110 P05046 — —1 0.52 0.25 0.05 0.03 0.07 0.06 0.00 0.03 0.04 0.02 0.03 0.05 0.12 0.06SEQID-01111 P19594 — — 1 0.43 0.15 0.02 0.08 0.04 0.09 0.06 0.08 0.120.02 0.04 0.07 0.08 0.10 SEQID-01112 K7MJY8 — — 1 0.49 0.23 0.04 0.080.04 0.05 0.01 0.04 0.10 0.03 0.04 0.06 0.11 0.06 SEQID-01113 P25698 — —1 0.52 0.21 0.04 0.06 0.03 0.06 0.01 0.02 0.07 0.04 0.03 0.07 0.06 0.13SEQID-01114 I7FST9 — — 1 0.46 0.18 0.05 0.03 0.04 0.07 0.01 0.05 0.100.03 0.03 0.05 0.06 0.10 SEQID-01115 C6T7Y1 — — 1 0.47 0.21 0.05 0.070.02 0.06 0.01 0.03 0.09 0.04 0.03 0.08 0.07 0.06 SEQID-01116 I1JPW5 — —1 0.47 0.23 0.07 0.04 0.06 0.07 0.01 0.04 0.08 0.05 0.01 0.06 0.08 0.10SEQID-01117 I1LN49 — — 1 0.48 0.18 0.03 0.03 0.03 0.04 0.02 0.05 0.090.03 0.08 0.05 0.10 0.06 SEQID-01118 C6TNT2 — — 1 0.48 0.19 0.05 0.040.05 0.06 0.01 0.04 0.09 0.02 0.01 0.05 0.09 0.11 SEQID-01119 O64458 — —1 0.45 0.18 0.04 0.05 0.04 0.06 0.02 0.05 0.08 0.04 0.04 0.06 0.08 0.08SEQID-01120 P01064 — — 0 0.28 0.08 0.00 0.03 0.02 0.13 0.16 0.05 0.030.01 0.01 0.02 0.06 0.07 SEQID-01121 C65WV3 — — 1 0.44 0.18 0.05 0.060.02 0.06 0.01 0.06 0.08 0.02 0.04 0.05 0.07 0.07 SEQID-01122 C6TKH0 — —1 0.45 0.20 0.07 0.04 0.07 0.05 0.03 0.07 0.07 0.04 0.03 0.05 0.08 0.08SEQID-01123 I1JGP8 — — 1 0.50 0.24 0.08 0.04 0.04 0.05 0.01 0.02 0.070.05 0.02 0.06 0.11 0.08 SEQID-01124 I1K668 — — 1 0.47 0.22 0.05 0.070.04 0.07 0.01 0.04 0.11 0.04 0.01 0.07 0.08 0.11 SEQID-01125 I1KAB7 — —1 0.47 0.20 0.05 0.03 0.05 0.07 0.01 0.05 0.11 0.03 0.03 0.05 0.07 0.10SEQID-01126 I1NFS4 — — 1 0.44 0.24 0.07 0.08 0.03 0.05 0.00 0.05 0.080.05 0.02 0.07 0.09 0.05 SEQID-01127 P25272 — — 1 0.48 0.24 0.04 0.060.03 0.07 0.02 0.05 0.06 0.04 0.01 0.07 0.10 0.06 SEQID-01128 H2D553 — —1 0.47 0.25 0.08 0.05 0.06 0.05 0.02 0.04 0.07 0.04 0.02 0.07 0.09 0.07SEQID-01129 I1JB84 — — 1 0.48 0.25 0.03 0.05 0.05 0.05 0.02 0.04 0.050.04 0.03 0.07 0.08 0.06 SEQID-01130 I1KTX8 — — 1 0.49 0.27 0.08 0.050.02 0.06 0.00 0.02 0.06 0.05 0.02 0.05 0.13 0.09 SEQID-01131 I1KU21 — —1 0.08 0.21 0.05 0.07 0.03 0.06 0.02 0.04 0.09 0.04 0.02 0.05 0.08 0.08SEQID-01132 I1L3K7 — — 1 0.45 0.22 0.07 0.04 0.05 0.06 0.01 0.05 0.080.05 0.02 0.06 0.08 0.10 SEQID-01133 I1K3X9 — — 1 0.44 0.21 0.05 0.070.04 0.06 0.02 0.03 0.09 0.04 0.04 0.06 0.08 0.05 SEQID-01134 I1LDR2 — —1 0.42 0.17 0.04 0.07 0.05 0.06 0.02 0.06 0.09 0.04 0.02 0.04 0.07 0.04SEQID-01135 O48548 — — 1 0.46 0.24 0.06 0.08 0.04 0.06 0.01 0.04 0.040.04 0.03 0.06 0.11 0.05 SEQID-01136 O22518 — — 1 0.42 0.19 0.08 0.070.04 0.07 0.01 0.08 0.06 0.04 0.02 0.08 0.06 0.04 SEQID-01137 Q01915 — —0 0.43 0.26 0.07 0.09 0.03 0.05 0.01 0.06 0.08 0.04 0.01 0.08 0.11 0.06SEQID-01138 Q42806 — — 1 0.50 0.25 0.06 0.06 0.04 0.06 0.02 0.02 0.070.04 0.02 0.07 0.10 0.09 SEQID-01139 D6C4Z9 — — 1 0.49 0.21 0.04 0.040.04 0.07 0.01 0.03 0.14 0.02 0.02 0.06 0.10 0.13 SEQID-01140 I1K3K3 — —1 0.48 0.23 0.06 0.06 0.05 0.07 0.01 0.03 0.06 0.05 0.03 0.08 0.08 0.07SEQID-01141 K7LEQ5 — — 0 0.40 0.07 0.03 0.05 0.05 0.09 0.00 0.06 0.030.11 0.09 0.03 0.01 0.06 SEQID-01142 P26413 — — 1 0.45 0.20 0.06 0.070.06 0.07 0.01 0.04 0.10 0.04 0.01 0.07 0.07 0.10 SEQID-01143 C6TG91 — —1 0.46 0.23 0.05 0.12 0.03 0.04 0.01 0.04 0.09 0.04 0.01 0.05 0.09 0.10SEQID-01144 I1NJ85 — — 1 0.48 0.24 0.07 0.05 0.04 0.06 0.02 0.03 0.050.05 0.03 0.07 0.09 0.07 SEQID-01145 K7M

E5 — — 1 0.51 0.25 0.07 0.05 0.06 0.03 0.01 0.04 0.09 0.04 0.02 0.060.06 0.08 SEQID-01146 Q9ZNZ1 — — 0 0.43 0.18 0.02 0.08 0.03 0.05 0.060.09 0.14 0.03 0.04 0.09 0.10 0.10 SEQID-01147 P27066 — — 1 0.46 0.190.06 0.09 0.03 0.06 0.02 0.03 0.09 0.05 0.04 0.04 0.09 0.06 SEQID-01148C6SVX5 — — 1 0.45 0.16 0.06 0.14 0.04 0.04 0.03 0.03 0.04 0.04 0.04 0.040.06 0.11 SEQID-01149 I1JUP4 — — 1 0.46 0.24 0.08 0.05 0.03 0.04 0.010.03 0.02 0.06 0.01 0.08 0.10 0.05 SEQID-01150 I1K354 — — 1 0.50 0.230.06 0.06 0.04 0.06 0.02 0.04 0.08 0.04 0.02 0.06 0.10 0.08 SEQID-01151I1K5E6 — — 1 0.49 0.23 0.05 0.08 0.04 0.08 0.02 0.02 0.03 0.04 0.03 0.060.10 0.06 SEQID-01152 I1KYW3 — — 1 0.46 0.21 0.04 0.05 0.04 0.06 0.030.05 0.05 0.04 0.02 0.08 0.09 0.07 SEQID-01153 I1LKD3 — — 1 0.49 0.200.05 0.06 0.03 0.06 0.01 0.03 0.09 0.04 0.03 0.05 0.10 0.08 SEQID-01154I1LQR8 — — 1 0.46 0.19 0.06 0.06 0.05 0.03 0.07 0.03 0.02 0.05 0.07 0.030.09 0.02 SEQID-01155 I1LUL9 — — 1 0.45 0.22 0.07 0.08 0.04 0.06 0.010.03 0.07 0.04 0.02 0.06 0.09 0.06 SEQID-01156 I1M1V8 — — 1 0.46 0.230.07 0.05 0.05 0.05 0.02 0.04 0.06 0.04 0.03 0.07 0.08 0.05 SEQID-01157K7KTR9 — — 1 0.46 0.23 0.06 0.06 0.03 0.04 0.01 0.04 0.02 0.05 0.02 0.080.11 0.03 SEQID-01158 Q8LJW0 — — 1 0.52 0.22 0.04 0.12 0.04 0.05 0.010.03 0.05 0.04 0.04 0.07 0.09 0.12 SEQID-01159 Q9XEY1 — — 1 0.42 0.180.03 0.12 0.05 0.10 0.02 0.05 0.09 0.03 0.03 0.04 0.06 0.09 SEQID-01160P28759 — — 1 0.49 0.20 0.05 0.03 0.06 0.05 0.00 0.04 0.08 0.04 0.02 0.040.10 0.09 SEQID-01161 C6SVT0 — — 1 0.46 0.23 0.04 0.06 0.05 0.05 0.030.06 0.08 0.03 0.02 0.04 0.10 0.09 SEQID-01162 C6T9B1 — — 1 0.48 0.200.06 0.07 0.05 0.08 0.01 0.02 0.08 0.05 0.12 0.06 0.09 0.05 SEQID-01163C6TGW2 — — 1 0.39 0.19 0.08 0.08 0.03 0.07 0.01 0.03 0.14 0.02 0.01 0.050.10 0.07 SEQID-01164 I1JXA0 — — 1 0.43 0.21 0.04 0.10 0.04 0.08 0.010.03 0.11 0.03 0.02 0.06 0.08 0.07 SEQID-01165 I1K4Q5 — — 1 0.52 0.210.05 0.07 0.03 0.04 0.00 0.03 0.06 0.04 0.02 0.04 0.03 0.18 SEQID-01166I1K5M9 — — 1 0.46 0.21 0.05 0.06 0.04 0.07 0.01 0.02 0.08 0.05 0.03 0.060.08 0.07 SEQID-01167 I1MAE7 — — 1 0.47 0.19 0.05 0.09 0.03 0.06 0.010.03 0.10 0.03 0.04 0.03 0.10 0.07 SEQID-01168 K7K4G2 — — 1 0.40 0.150.03 0.13 0.04 0.04 0.01 0.05 0.20 0.03 0.02 0.04 0.07 0.10 SEQID-01169K7MX62 — — 0 0.53 0.18 0.06 0.05 0.04 0.05 0.00 0.02 0.10 0.03 0.02 0.030.05 0.15 SEQID-01170 P05478 — — 1 0.48 0.17 0.03 0.08 0.06 0.07 0.000.02 0.12 0.02 0.01 0.04 0.04 0.11 SEQID-01171 C6SY27 — — 0 0.52 0.240.05 0.14 0.03 0.08 0.00 0.03 0.04 0.01 0.00 0.07 0.07 0.17 SEQID-01172C6T9D7 — — 1 0.46 0.20 0.05 0.07 0.05 0.05 0.01 0.04 0.08 0.04 0.02 0.050.08 0.08 SEQID-01173 I1JFX0 — — 1 0.49 0.22 0.06 0.05 0.03 0.04 0.010.04 0.07 0.04 0.05 0.05 0.08 0.07 SEQID-01174 I1KGP0 — — 1 0.49 0.220.04 0.11 0.06 0.03 0.00 0.03 0.10 0.03 0.02 0.07 0.10 0.14 SEQID-01175I1KJI7 — — 1 0.49 0.22 0.05 0.07 0.03 0.05 0.00 0.04 0.08 0.05 0.02 0.100.05 0.07 SEQID-01176 I1L8R1 — — 1 0.46 0.19 0.07 0.12 0.04 0.04 0.000.03 0.05 0.03 0.02 0.05 0.07 0.13 SEQID-01177 I1LID6 — — 1 0.45 0.180.07 0.14 0.04 0.04 0.01 0.03 0.03 0.07 0.07 0.05 0.05 0.09 SEQID-01178I1LWR4 — — 1 0.45 0.20 0.06 0.07 0.05 0.05 0.01 0.03 0.11 0.03 0.02 0.060.08 0.08 SEQID-01179 I1M561 — — 1 0.49 0.25 0.08 0.06 0.04 0.06 0.010.01 0.09 0.05 0.02 0.05 0.13 0.08 SEQID-01180 I1

E4 — — 1 0.45 0.24 0.06 0.06 0.04 0.07 0.01 0.04 0.06 0.03 0.02 0.060.11 0.07 SEQID-01181 K7KN32 — — 1 0.49 0.27 0.05 0.07 0.05 0.05 0.010.04 0.04 0.03 0.03 0.09 0.12 0.04 SEQID-01182 Q42807 — — 1 0.44 0.180.04 0.10 0.03 0.06 0.01 0.05 0.10 0.03 0.03 0.06 0.08 0.07 SEQID-01183A0A762 — — 1 0.43 0.14 0.04 0.03 0.04 0.12 0.01 0.02 0.13 0.03 0.02 0.040.06 0.12 SEQID-01184 C6SZ13 — — 1 0.50 0.28 0.09 0.05 0.01 0.04 0.000.10 0.02 0.03 0.04 0.08 0.11 0.04 SEQID-01185 C6T1V2 — — 1 0.47 0.170.03 0.10 0.04 0.06 0.00 0.04 0.11 0.04 0.02 0.04 0.04 0.09 SEQID-01186I1JDH6 — — 1 0.48 0.20 0.03 0.14 0.02 0.04 0.01 0.03 0.07 0.07 0.02 0.050.07 0.10 SEQID-01187 I1KUR0 — — 1 0.46 0.23 0.03 0.10 0.03 0.08 0.010.08 0.07 0.04 0.01 0.06 0.10 0.05 SEQID-01188 I1KZP9 — — 1 0.54 0.180.04 0.10 0.02 0.03 0.01 0.04 0.07 0.04 0.06 0.05 0.06 0.15 SEQID-01189I1LLR5 — — 1 0.48 0.20 0.04 0.02 0.04 0.04 0.04 0.04 0.09 0.01 0.05 0.040.11 0.07 SEQID-01190 I1M3C1 — — 0 0.42 0.18 0.07 0.11 0.03 0.07 0.000.02 0.10 0.03 0.03 0.05 0.08 0.12 SEQID-01191 I1MUH0 — — 1 0.51 0.280.08 0.07 0.01 0.05 0.01 0.02 0.01 0.04 0.03 0.04 0.16 0.03 SEQID-01192P04670 — — 1 0.50 0.21 0.04 0.06 0.03 0.05 0.01 0.05 0.08 0.03 0.03 0.050.08 0.08 SEQID-01193 P17093 — — 1 0.52 0.17 0.04 0.11 0.04 0.01 0.020.03 0.04 0.05 0.04 0.08 0.04 0.15 SEQID-01194 Q9SWB6 — — 1 0.50 0.200.05 0.04 0.04 0.04 0.02 0.04 0.12 0.03 0.02 0.06 0.09 0.09 SEQID-01195C6F117 — — 1 0.51 0.25 0.03 0.12 0.04 0.04 0.01 0.03 0.07 0.05 0.03 0.070.08 0.10 SEQID-01196 C6K8D0 — — 1 0.48 0.25 0.04 0.06 0.04 0.04 0.020.04 0.05 0.05 0.02 0.06 0.10 0.06 SEQID-01197 C6SWG9 — — 1 0.43 0.170.06 0.14 0.04 0.03 0.02 0.05 0.07 0.02 0.04 0.04 0.08 0.12 SEQID-01198C6SXS0 — — 1 0.46 0.22 0.03 0.14 0.03 0.04 0.01 0.05 0.07 0.04 0.01 0.060.08 0.10 SEQID-01199 C6SZX7 — — 1 0.48 0.20 0.05 0.03 0.09 0.07 0.020.03 0.06 0.04 0.01 0.04 0.09 0.12 SEQID-01200 C6T034 — — 1 0.47 0.200.08 0.03 0.01 0.10 0.01 0.03 0.11 0.03 0.01 0.05 0.08 0.12 SEQID-01201C6T048 — — 1 0.50 0.19 0.04 0.14 0.06 0.07 0.01 0.04 0.03 0.04 0.03 0.050.08 0.13 SEQID-01202 C6T871 — — 1 0.50 0.23 0.05 0.09 0.05 0.03 0.010.02 0.08 0.04 0.03 0.06 0.10 0.03 SEQID-01203 C6T9G0 — — 1 0.44 0.200.05 0.06 0.07 0.07 0.02 0.06 0.06 0.03 0.01 0.07 0.07 0.07 SEQID-01204C5TFI8 — — 1 0.47 0.19 0.03 0.18 0.03 0.06 0.00 0.02 0.05 0.02 0.02 0.030.04 0.14 SEQID-01205 C6THM2 — — 1 0.48 0.20 0.06 0.07 0.03 0.05 0.010.04 0.07 0.03 0.06 0.06 0.10 0.09 SEQID-01206 C6TJH2 — — 1 0.53 0.250.02 0.09 0.05 0.06 0.01 0.01 0.08 0.04 0.04 0.09 0.08 0.12 SEQID-01207I1JW44 — — 1 0.46 0.23 0.06 0.06 0.05 0.04 0.03 0.05 0.02 0.03 0.01 0.040.11 0.04 SEQID-01208 I1JX58 — — 1 0.41 0.20 0.06 0.10 0.04 0.06 0.010.05 0.09 0.04 0.01 0.04 0.08 0.07 SEQID-01209 I1K3R6 — — 1 0.47 0.210.03 0.05 0.03 0.07 0.02 0.03 0.06 0.05 0.05 0.05 0.10 0.05 SEQID-01210I1K467 — — 0 0.49 0.26 0.08 0.07 0.03 0.07 0.01 0.04 0.09 0.03 0.02 0.070.10 0.09 SEQID-01211 I1K554 — — 0 0.45 0.18 0.03 0.19 0.00 0.05 0.100.05 0.03 0.05 0.03 0.01 0.12 0.06 SEQID-01212 I1KDM8 — — 0 0.48 0.250.08 0.05 0.04 0.05 0.01 0.03 0.06 0.06 0.02 0.05 0.11 0.09 SEQID-01213I1KRJ7 — — 1 0.51 0.21 0.03 0.04 0.04 0.07 0.01 0.05 0.07 0.03 0.02 0.060.09 0.11 SEQID-01214 I1KZT2 — — 1 0.48 0.21 0.04 0.07 0.03 0.06 0.010.03 0.10 0.04 0.02 0.05 0.08 0.09 SEQID-01215 I1LCQ1 — — 1 0.52 0.260.05 0.06 0.03 0.06 0.01 0.03 0.08 0.03 0.03 0.08 0.11 0.09 SEQID-01216I1M322 — — 1 0.50 0.27 0.08 0.06 0.04 0.05 0.01 0.02 0.08 0.03 0.02 0.050.12 0.08 SEQID-01217 I1MC31 — — 1 0.47 0.20 0.03 0.06 0.04 0.09 0.000.03 0.12 0.02 0.01 0.05 0.10 0.12 SEQID-01218 K7LSN8 — — 1 0.50 0.190.05 0.05 0.05 0.03 0.02 0.03 0.05 0.06 0.03 0.06 0.05 0.07 SEQID-01219K7M

Y6 — — 1 0.52 0.26 0.04 0.07 0.02 0.08 0.02 0.04 0.06 0.03 0.05 0.060.11 0.06 SEQID-01220 A1VZE0 — — 1 0.49 0.23 0.05 0.06 0.04 0.06 0.010.04 0.06 0.05 0.02 0.06 0.08 0.08 SEQID-01221 B2BF98 — — 1 0.45 0.180.05 0.17 0.02 0.05 0.01 0.04 0.06 0.04 0.00 0.04 0.09 0.16 SEQID-01222C6SV94 — — 0 0.43 0.19 0.07 0.18 0.02 0.06 0.01 0.02 0.06 0.05 0.03 0.060.07 0.08 SEQID-01223 C63VR

— — 1 0.44 0.18 0.06 0.14 0.01 0.05 0.01 0.04 0.04 0.05 0.03 0.06 0.060.09 SEQID-01224 C6SVS3 — — 1 0.56 0.23 0.04 0.04 0.05 0.03 0.02 0.060.07 0.03 0.02 0.05 0.12 0.17 SEQID-01225 C6SWA6 — — 0 0.46 0.23 0.080.11 0.04 0.02 0.00 0.02 0.06 0.07 0.02 0.04 0.11 0.17 SEQID-01226C6SWE0 — — 1 0.54 0.27 0.07 0.03 0.04 0.06 0.01 0.01 0.10 0.05 0.02 0.080.10 0.11 SEQID-01227 C6SWG3 — — 0 0.50 0.19 0.06 0.13 0.02 0.04 0.000.02 0.07 0.04 0.03 0.07 0.07 0.12 SEQID-01228 C6T065 — — 0 0.47 0.220.05 0.03 0.05 0.07 0.02 0.05 0.06 0.05 0.04 0.06 0.08 0.08 SEQID-01229C6T0U3 — — 1 0.52 0.23 0.03 0.10 0.02 0.05 0.01 0.03 0.08 0.03 0.04 0.070.07 0.12 SEQID-01230 C6T530 — — 0 0.47 0.22 0.04 0.13 0.03 0.06 0.000.02 0.09 0.02 0.02 0.05 0.08 0.12 SEQID-01231 C6T5U0 — — 0 0.43 0.220.07 0.15 0.01 0.03 0.02 0.05 0.06 0.05 0.02 0.09 0.06 0.10 SEQID-01232C6THA9 — — 1 0.47 0.22 0.02 0.09 0.06 0.05 0.01 0.03 0.08 0.04 0.03 0.070.09 0.07 SEQID-01233 C6TI64 — — 1 0.52 0.20 0.05 0.09 0.03 0.07 0.010.05 0.07 0.03 0.02 0.06 0.06 0.15 SEQID-01234 C6TMB5 — — 1 0.50 0.260.05 0.07 0.03 0.09 0.01 0.04 0.07 0.04 0.01 0.08 0.08 0.14 SEQID-01235I1JA95 — — 1 0.37 0.12 0.03 0.13 0.03 0.06 0.01 0.03 0.06 0.09 0.01 0.050.05 0.08 SEQID-01236 I1JSJ3 — — 1 0.44 0.23 0.08 0.06 0.05 0.04 0.010.05 0.08 0.04 0.01 0.04 0.12 0.07 SEQID-01237 I1JXS7 — — 1 0.45 0.180.04 0.04 0.04 0.09 0.01 0.02 0.12 0.03 0.02 0.07 0.07 0.11 SEQID-01238I1K099 — — 1 0.46 0.21 0.06 0.08 0.02 0.05 0.01 0.03 0.09 0.04 0.02 0.050.10 0.08 SEQID-01239 I1K1K4 — — 1 0.55 0.27 0.08 0.05 0.01 0.01 0.010.09 0.04 0.05 0.06 0.04 0.15 0.02 SEQID-01240 I1K964 — — 1 0.45 0.230.05 0.05 0.05 0.06 0.00 0.06 0.05 0.06 0.03 0.06 0.08 0.05 SEQID-01241I1K9I0 — — 1 0.45 0.22 0.04 0.07 0.05 0.07 0.02 0.04 0.06 0.04 0.03 0.080.07 0.07 SEQID-01242 I1K9M9 — — 1 0.45 0.23 0.04 0.05 0.05 0.04 0.030.04 0.03 0.04 0.01 0.06 0.10 0.04 SEQID-01243 I1KG34 — — 1 0.45 0.210.06 0.07 0.03 0.06 0.01 0.04 0.08 0.04 0.02 0.05 0.10 0.06 SEQID-01244I1KZY9 — — 1 0.47 0.23 0.04 0.05 0.05 0.05 0.01 0.04 0.06 0.04 0.04 0.050.12 0.05 SEQID-01245 I1L0S5 — — 1 0.49 0.23 0.09 0.04 0.07 0.03 0.010.03 0.08 0.06 0.03 0.05 0.14 0.07 SEQID-01246 I1L5Q0 — — 1 0.46 0.200.05 0.12 0.04 0.05 0.01 0.05 0.11 0.02 0.02 0.05 0.10 0.12 SEQID-01247I1L957 — — 0 0.38 0.09 0.11 0.06 0.03 0.08 0.00 0.05 0.15 0.04 0.01 0.010.02 0.18 SEQID-01248 I1LFD6 — — 1 0.55 0.26 0.05 0.01 0.03 0.04 0.000.01 0.09 0.03 0.04 0.04 0.12 0.11 SEQID-01249 I1LIT1 — — 1 0.46 0.230.03 0.06 0.04 0.06 0.00 0.02 0.05 0.05 0.01 0.08 0.09 0.08 SEQID-01250I1MIA3 — — 0 0.44 0.22 0.06 0.10 0.03 0.14 0.00 0.03 0.08 0.03 0.01 0.050.10 0.05 SEQID-01251 I1N1F9 — — 1 0.48 0.21 0.07 0.06 0.03 0.05 0.010.04 0.07 0.05 0.03 0.05 0.09 0.07 SEQID-01252 I1N4U1 — — 1 0.45 0.220.06 0.07 0.04 0.06 0.01 0.04 0.09 0.05 0.01 0.08 0.09 0.09 SEQID-01253I1NH02 — — 1 0.45 0.20 0.04 0.02 0.06 0.07 0.02 0.06 0.03 0.04 0.03 0.050.10 0.05 SEQID-01254 O23957 — — 0 0.40 0.13 0.06 0.09 0.05 0.05 0.000.05 0.07 0.08 0.06 0.03 0.06 0.08 SEQID-01255 O49857 — — 1 0.47 0.220.03 0.06 0.06 0.04 0.02 0.04 0.08 0.04 0.03 0.06 0.09 0.05 SEQID-01256P00560 — — 1 0.51 0.25 0.07 0.05 0.04 0.07 0.00 0.02 0.08 0.05 0.02 0.060.10 0.12 SEQID-01257 P00359 — — 1 0.50 0.23 0.06 0.05 0.04 0.08 0.010.02 0.05 0.04 0.03 0.06 0.07 0.09 SEQID-01258 P00549 — — 1 0.43 0.240.06 0.07 0.05 0.07 0.01 0.02 0.07 0.04 0.02 0.08 0.07 0.09 SEQID-01259P00358 — — 1 0.51 0.23 0.07 0.05 0.04 0.08 0.01 0.02 0.05 0.04 0.03 0.060.07 0.09 SEQID-01260 P10591 — — 1 0.45 0.20 0.06 0.06 0.05 0.08 0.000.04 0.09 0.04 0.01 0.06 0.08 0.10 SEQID-01261 P00360 — — 1 0.51 0.230.07 0.05 0.03 0.08 0.01 0.03 0.04 0.04 0.03 0.07 0.06 0.10 SEQID-01262P10592 — — 1 0.45 0.20 0.06 0.06 0.05 0.08 0.00 0.04 0.10 0.04 0.01 0.060.08 0.10 SEQID-01263 P00942 — — 1 0.49 0.24 0.07 0.05 0.05 0.06 0.010.03 0.08 0.05 0.02 0.06 0.08 0.10 SEQID-01264 P02994 — — 1 0.52 0.210.05 0.06 0.04 0.06 0.01 0.03 0.08 0.05 0.03 0.07 0.05 0.13 SEQID-01265P06169 — — 1 0.51 0.23 0.06 0.04 0.05 0.05 0.01 0.05 0.06 0.04 0.03 0.070.10 0.07 SEQID-01266 P22943 — — 0 0.35 0.10 0.08 0.04 0.03 0.11 0.000.07 0.12 0.06 0.02 0.01 0.03 0.16 SEQID-01267 P14540 — — 1 0.47 0.190.06 0.04 0.05 0.05 0.01 0.03 0.10 0.04 0.04 0.07 0.07 0.09 SEQID-01268P05694 — — 1 0.48 0.22 0.05 0.06 0.05 0.06 0.00 0.04 0.08 0.03 0.02 0.060.09 0.09 SEQID-01269 P31539 — — 0 0.44 0.23 0.05 0.08 0.04 0.08 0.010.07 0.10 0.03 0.02 0.08 0.11 0.09 SEQID-01270 P15108 — — 1 0.48 0.210.04 0.05 0.04 0.07 0.00 0.03 0.15 0.02 0.01 0.07 0.10 0.12 SEQID-01271P32324 — — 1 0.49 0.23 0.05 0.07 0.03 0.07 0.01 0.04 0.08 0.04 0.02 0.060.08 0.08 SEQID-01272 Q07653 — — 1 0.38 0.09 0.04 0.05 0.08 0.08 0.000.05 0.07 0.04 0.06 0.03 0.02 0.09 SEQID-01273 P34730 — — 1 0.37 0.170.05 0.06 0.03 0.05 0.00 0.12 0.13 0.01 0.02 0.05 0.09 0.07 SEQID-01274P02829 — — 1 0.48 0.21 0.04 0.05 0.04 0.07 0.00 0.03 0.15 0.02 0.01 0.070.09 0.12 SEQID-01275 Q08969 — — 1 0.25 0.05 0.01 0.10 0.09 0.13 0.000.17 0.06 0.07 0.03 0.01 0.04 0.03 SEQID-01276 P46367 — — 1 0.48 0.230.05 0.05 0.05 0.05 0.01 0.04 0.08 0.05 0.02 0.09 0.07 0.09 SEQID-01277P00950 — — 1 0.45 0.22 0.06 0.07 0.05 0.07 0.00 0.04 0.08 0.03 0.02 0.050.11 0.11 SEQID-01278 P14126 — — 1 0.52 0.18 0.05 0.12 0.02 0.04 0.000.02 0.06 0.04 0.05 0.05 0.05 0.13 SEQID-01279 P06106 — — 1 0.47 0.200.06 0.04 0.05 0.05 0.00 0.05 0.07 0.05 0.05 0.06 0.08 0.07 SEQID-01280P17709 — — 1 0.50 0.23 0.04 0.06 0.03 0.07 0.01 0.04 0.08 0.04 0.04 0.060.12 0.07 SEQID-01281 P38158 — — 1 0.48 0.15 0.09 0.06 0.05 0.08 0.010.03 0.08 0.03 0.03 0.06 0.06 0.09 SEQID-01282 Q12230 — — 1 0.39 0.190.06 0.07 0.03 0.08 0.00 0.05 0.14 0.02 0.03 0.04 0.09 0.07 SEQID-01283P07251 — — 1 0.43 0.26 0.07 0.09 0.04 0.04 0.00 0.06 0.08 0.05 0.01 0.060.13 0.06 SEQID-01284 P11484 — — 1 0.47 0.22 0.07 0.07 0.04 0.07 0.000.05 0.10 0.04 0.01 0.06 0.09 0.09 SEQID-01285 P17536 — — 1 0.40 0.180.03 0.04 0.07 0.06 0.00 0.08 0.25 0.00 0.02 0.03 0.12 0.15 SEQID-01286P60010 — — 1 0.47 0.21 0.04 0.07 0.02 0.06 0.01 0.04 0.08 0.04 0.03 0.060.07 0.06 SEQID-01287 P12709 — — 1 0.53 0.20 0.06 0.03 0.07 0.05 0.000.04 0.07 0.04 0.04 0.06 0.09 0.08 SEQID-01288 P09435 — — 1 0.44 0.190.06 0.08 0.05 0.08 0.00 0.04 0.09 0.04 0.01 0.06 0.07 0.08 SEQID-01289P19414 — — 1 0.48 0.20 0.06 0.06 0.06 0.08 0.01 0.03 0.06 0.05 0.03 0.070.08 0.10 SEQID-01290 P17255 — — 1 0.46 0.21 0.05 0.07 0.04 0.06 0.010.03 0.09 0.04 0.02 0.06 0.08 0.08 SEQID-01291 P19882 — — 0 0.46 0.250.07 0.07 0.03 0.06 0.01 0.03 0.11 0.05 0.00 0.08 0.09 0.09 SEQID-01292P16467 — — 1 0.51 0.24 0.06 0.05 0.05 0.05 0.01 0.04 0.07 0.04 0.03 0.070.10 0.07 SEQID-01293 P06115 — — 1 0.43 0.16 0.03 0.06 0.06 0.06 0.010.07 0.07 0.03 0.03 0.04 0.06 0.08 SEQID-01294 Q00055 — — 1 0.48 0.240.05 0.05 0.05 0.05 0.02 0.04 0.10 0.05 0.04 0.07 0.08 0.07 SEQID-01295P04806 — — 1 0.48 0.22 0.04 0.05 0.04 0.08 0.01 0.04 0.08 0.04 0.02 0.070.10 0.09 SEQID-01296 P16862 — — 1 0.44 0.21 0.07 0.08 0.05 0.06 0.010.03 0.07 0.04 0.02 0.06 0.08 0.06 SEQID-01297 P0CX36 — — 1 0.51 0.240.04 0.12 0.04 0.07 0.00 0.02 0.04 0.05 0.05 0.06 0.10 0.12 SEQID-01298P53252 — — 1 0.35 0.18 0.05 0.08 0.02 0.08 0.00 0.08 0.15 0.03 0.01 0.060.09 0.07 SEQID-01299 P00830 — — 1 0.48 0.25 0.07 0.07 0.02 0.05 0.000.05 0.09 0.05 0.02 0.07 0.10 0.07 SEQID-01300 P16861 — — 1 0.48 0.220.06 0.07 0.05 0.06 0.01 0.03 0.08 0.04 0.03 0.06 0.09 0.07 SEQID-01301P16521 — — 1 0.49 0.22 0.06 0.06 0.05 0.06 0.01 0.03 0.10 0.03 0.03 0.080.08 0.09 SEQID-01302 P11154 — — 1 0.46 0.23 0.06 0.08 0.04 0.07 0.010.05 0.07 0.04 0.03 0.06 0.09 0.06 SEQID-01303 P23301 — — 0 0.50 0.180.05 0.04 0.03 0.11 0.01 0.02 0.09 0.04 0.04 0.05 0.07 0.10 SEQID-01304P41805 — — 1 0.43 0.18 0.06 0.14 0.04 0.05 0.02 0.04 0.06 0.03 0.03 0.040.08 0.11 SEQID-01305 P00331 — — 1 0.47 0.23 0.07 0.03 0.04 0.05 0.020.02 0.07 0.07 0.04 0.07 0.08 0.08 SEQID-01306 P10081 — — 0 0.47 0.240.04 0.06 0.04 0.07 0.01 0.06 0.09 0.03 0.01 0.08 0.09 0.06 SEQID-01307P18899 — — 0 0.13 0.02 0.00 0.02 0.25 0.14 0.00 0.02 0.01 0.06 0.00 0.010.00 0.03 SEQID-01308 Q12363 — — 1 0.47 0.19 0.03 0.05 0.05 0.08 0.000.03 0.07 0.03 0.03 0.07 0.06 0.07 SEQID-01309 Q12122 — — 1 0.48 0.230.05 0.06 0.06 0.09 0.02 0.02 0.06 0.03 0.03 0.09 0.07 0.09 SEQID-01310P07262 — — 1 0.43 0.20 0.05 0.06 0.05 0.04 0.01 0.05 0.09 0.06 0.01 0.070.06 0.07 SEQID-01311 P37291 — — 1 0.46 0.21 0.05 0.07 0.04 0.06 0.010.04 0.07 0.04 0.04 0.07 0.08 0.08 SEQID-01312 P00890 — — 1 0.48 0.220.05 0.06 0.03 0.04 0.00 0.04 0.09 0.04 0.03 0.05 0.12 0.09 SEQID-01313P38720 — — 1 0.47 0.22 0.06 0.06 0.04 0.07 0.01 0.03 0.07 0.05 0.02 0.080.09 0.08 SEQID-01314 P26263 — — 1 0.52 0.26 0.05 0.03 0.05 0.05 0.000.05 0.07 0.04 0.03 0.07 0.12 0.08 SEQID-01315 P33315 — — 1 0.45 0.200.05 0.06 0.04 0.06 0.00 0.05 0.07 0.05 0.03 0.05 0.09 0.07 SEQID-01316P07149 — — 1 0.50 0.23 0.04 0.05 0.05 0.06 0.01 0.04 0.08 0.03 0.02 0.070.09 0.08 SEQID-01317 P0CX48 — — 1 0.54 0.19 0.04 0.11 0.05 0.01 0.010.04 0.03 0.03 0.04 0.06 0.03 0.14 SEQID-01318 P15992 — — 1 0.44 0.190.03 0.05 0.09 0.10 0.00 0.03 0.06 0.04 0.02 0.04 0.08 0.11 SEQID-01319P26783 — — 1 0.45 0.23 0.07 0.11 0.06 0.05 0.00 0.06 0.10 0.02 0.01 0.080.06 0.08 SEQID-01320 P35719 — — 1 0.48 0.23 0.03 0.06 0.04 0.11 0.000.05 0.13 0.02 0.01 0.06 0.12 0.12 SEQID-01321 P33442 — — 1 0.55 0.220.04 0.03 0.04 0.05 0.00 0.05 0.07 0.03 0.03 0.06 0.09 0.15 SEQID-01322P23248 — — 1 0.55 0.23 0.04 0.09 0.05 0.05 0.00 0.04 0.07 0.03 0.03 0.050.09 0.15 SEQID-01323 P33011 — — 1 0.51 0.21 0.07 0.04 0.05 0.08 0.010.04 0.03 0.04 0.03 0.05 0.09 0.07 SEQID-01324 P15019 — — 1 0.50 0.230.06 0.04 0.03 0.07 0.01 0.04 0.09 0.03 0.01 0.07 0.08 0.12 SEQID-01325P0C590 — — 1 0.46 0.23 0.06 0.07 0.06 0.06 0.00 0.05 0.10 0.04 0.01 0.070.08 0.09 SEQID-01326 P31688 — — 1 0.48 0.21 0.03 0.07 0.06 0.07 0.010.06 0.07 0.02 0.02 0.05 0.10 0.09 SEQID-01327 Q02326 — — 1 0.52 0.230.06 0.03 0.05 0.03 0.00 0.04 0.08 0.02 0.01 0.03 0.11 0.17 SEQID-01328P25443 — — 1 0.48 0.23 0.05 0.10 0.04 0.03 0.00 0.06 0.06 0.06 0.01 0.070.09 0.09 SEQID-01329 P05750 — — 0 0.45 0.23 0.08 0.12 0.02 0.04 0.000.03 0.11 0.04 0.01 0.06 0.08 0.09 SEQID-01330 P05317 — — 1 0.45 0.240.08 0.06 0.05 0.06 0.00 0.02 0.10 0.04 0.02 0.06 0.08 0.06 SEQID-01331P38009 — — 1 0.44 0.23 0.07 0.07 0.04 0.06 0.01 0.04 0.08 0.03 0.03 0.070.08 0.08 SEQID-01332 Q3E754 — — 0 0.34 0.21 0.05 0.11 0.07 0.08 0.010.04 0.08 0.04 0.01 0.06 0.08 0.07 SEQID-01333 P0C2H7 — — 1 0.57 0.180.06 0.08 0.02 0.01 0.00 0.03 0.07 0.03 0.05 0.03 0.04 0.19 SEQID-01334P35691 — — 1 0.49 0.19 0.05 0.02 0.05 0.10 0.01 0.03 0.10 0.04 0.01 0.070.04 0.10 SEQID-01335 Q12690 — — 1 0.41 0.17 0.10 0.18 0.05 0.03 0.000.05 0.08 0.02 0.02 0.05 0.06 0.11 SEQID-01336 P10664 — — 1 0.49 0.210.08 0.10 0.05 0.02 0.00 0.04 0.05 0.04 0.04 0.04 0.08 0.10 SEQID-01337P41939 — — 1 0.51 0.22 0.04 0.06 0.02 0.07 0.00 0.04 0.09 0.03 0.03 0.080.07 0.09 SEQID-01338 P16140 — — 1 0.43 0.22 0.04 0.09 0.05 0.07 0.000.04 0.10 0.04 0.02 0.08 0.08 0.06 SEQID-01339 P10963 — — 1 0.47 0.190.05 0.05 0.05 0.05 0.02 0.03 0.08 0.03 0.04 0.07 0.07 0.07 SEQID-01340P37012 — — 1 0.48 0.20 0.04 0.04 0.05 0.07 0.01 0.03 0.07 0.05 0.04 0.080.07 0.10 SEQID-01341 P23254 — — 1 0.46 0.21 0.07 0.05 0.05 0.05 0.000.04 0.06 0.04 0.03 0.06 0.10 0.07 SEQID-01342 P0CX52 — — 0 0.49 0.220.05 0.10 0.02 0.04 0.00 0.05 0.05 0.04 0.03 0.06 0.08 0.14 SEQID-01343P05759 — — 0 0.54 0.21 0.02 0.07 0.03 0.05 0.02 0.04 0.05 0.04 0.04 0.050.09 0.19 SEQID-01344 P0CX23 — — 1 0.50 0.18 0.04 0.12 0.03 0.03 0.000.04 0.06 0.01 0.05 0.06 0.05 0.12 SEQID-01345 P34760 — — 1 0.50 0.240.06 0.04 0.04 0.06 0.01 0.04 0.09 0.03 0.01 0.07 0.09 0.08 SEQID-01346P0CX45 — — 1 0.43 0.21 0.06 0.15 0.05 0.04 0.00 0.04 0.04 0.07 0.05 0.070.07 0.09 SEQID-01347 P46654 — — 1 0.42 0.22 0.08 0.08 0.05 0.05 0.000.04 0.12 0.02 0.02 0.06 0.08 0.03 SEQID-01348 P31116 — — 1 0.52 0.260.06 0.03 0.04 0.07 0.00 0.02 0.06 0.04 0.01 0.07 0.09 0.11 SEQID-01349P53912 — — 1 0.50 0.25 0.06 0.03 0.04 0.07 0.01 0.04 0.07 0.04 0.03 0.090.09 0.11 SEQID-01350 P19358 — — 1 0.46 0.21 0.06 0.06 0.02 0.09 0.010.05 0.07 0.04 0.02 0.07 0.08 0.09 SEQID-01351 P06168 — — 1 0.45 0.190.05 0.09 0.05 0.05 0.01 0.03 0.08 0.04 0.02 0.05 0.09 0.08 SEQID-01352Q03558 — — 1 0.42 0.18 0.06 0.08 0.06 0.05 0.00 0.04 0.09 0.04 0.02 0.060.07 0.07 SEQID-01353 P39954 — — 1 0.50 0.24 0.07 0.05 0.04 0.05 0.020.04 0.08 0.04 0.04 0.07 0.09 0.08 SEQID-01354 Q00764 — — 1 0.50 0.230.03 0.04 0.06 0.05 0.01 0.04 0.08 0.03 0.04 0.06 0.09 0.07 SEQID-01355P17967 — — 1 0.44 0.21 0.07 0.02 0.05 0.09 0.01 0.04 0.11 0.02 0.03 0.050.09 0.08 SEQID-01356 P04802 — — 1 0.45 0.20 0.05 0.09 0.03 0.06 0.000.05 0.12 0.03 0.03 0.05 0.10 0.10 SEQID-01357 P48589 — — 1 0.50 0.300.06 0.06 0.04 0.05 0.00 0.04 0.15 0.04 0.02 0.04 0.11 0.07 SEQID-01358P14832 — — 1 0.48 0.18 0.04 0.04 0.05 0.07 0.01 0.03 0.05 0.08 0.03 0.050.05 0.09 SEQID-01359 P0CX83 — — 1 0.42 0.18 0.09 0.20 0.04 0.04 0.000.04 0.07 0.02 0.04 0.04 0.08 0.14 SEQID-01360 P0CX39 — — 1 0.42 0.140.07 0.15 0.04 0.02 0.01 0.04 0.08 0.04 0.02 0.06 0.05 0.13 SEQID-01361P26786 — — 0 0.50 0.25 0.04 0.09 0.02 0.04 0.00 0.08 0.09 0.02 0.03 0.060.11 0.11 SEQID-01362 P05737 — — 1 0.48 0.22 0.06 0.08 0.06 0.02 0.000.06 0.07 0.03 0.02 0.09 0.08 0.13 SEQID-01363 P17076 — — 1 0.49 0.190.09 0.07 0.05 0.04 0.00 0.04 0.06 0.03 0.01 0.04 0.08 0.16 SEQID-01364P07283 — — 1 0.48 0.20 0.03 0.07 0.04 0.06 0.01 0.03 0.11 0.04 0.02 0.050.10 0.08 SEQID-01365 P00917 — — 1 0.49 0.20 0.05 0.03 0.06 0.09 0.000.03 0.08 0.03 0.03 0.09 0.06 0.12 SEQID-01366 P18239 — — 0 0.50 0.210.07 0.07 0.03 0.05 0.01 0.04 0.03 0.06 0.00 0.04 0.11 0.10 SEQID-01367P26321 — — 1 0.41 0.16 0.07 0.10 0.01 0.06 0.00 0.05 0.10 0.03 0.02 0.050.08 0.08 SEQID-01368 P17505 — — 0 0.51 0.25 0.06 0.05 0.06 0.05 0.000.02 0.07 0.04 0.03 0.07 0.10 0.10 SEQID-01369 P07257 — — 0 0.47 0.250.06 0.06 0.05 0.07 0.00 0.03 0.07 0.03 0.01 0.03 0.13 0.10 SEQID-01370P31373 — — 1 0.48 0.24 0.07 0.05 0.06 0.06 0.00 0.05 0.06 0.04 0.05 0.060.11 0.07 SEQID-01371 P38999 — — 1 0.48 0.23 0.06 0.05 0.03 0.08 0.010.02 0.07 0.04 0.01 0.06 0.10 0.09 SEQID-01372 P07256 — — 1 0.49 0.230.05 0.05 0.08 0.05 0.00 0.05 0.06 0.03 0.02 0.05 0.12 0.08 SEQID-01373P53319 — — 1 0.48 0.12 0.07 0.07 0.04 0.07 0.01 0.03 0.06 0.05 0.03 0.080.09 0.08 SEQID-01374 P54115 — — 1 0.48 0.22 0.06 0.05 0.06 0.06 0.010.03 0.09 0.05 0.01 0.07 0.08 0.09 SEQID-01375 P32861 — — 1 0.50 0.250.03 0.07 0.07 0.06 0.01 0.03 0.07 0.03 0.04 0.07 0.12 0.08 SEQID-01376P32191 — — 1 0.49 0.21 0.05 0.06 0.05 0.06 0.01 0.04 0.06 0.03 0.02 0.050.09 0.07 SEQID-01377 P19097 — — 1 0.46 0.21 0.06 0.05 0.04 0.05 0.000.05 0.10 0.04 0.02 0.06 0.09 0.09 SEQID-01378 P38711 — — 0 0.53 0.210.05 0.07 0.01 0.03 0.06 0.04 0.04 0.03 0.05 0.01 0.11 0.10 SEQID-01379P0CX31 — — 0 0.46 0.19 0.06 0.14 0.04 0.05 0.00 0.04 0.07 0.03 0.01 0.020.07 0.16 SEQID-01380 P0C0W1 — — 1 0.51 0.25 0.04 0.10 0.05 0.04 0.010.04 0.05 0.04 0.04 0.10 0.08 0.10 SEQID-01381 P39516 — — 0 0.42 0.190.09 0.16 0.02 0.07 0.01 0.03 0.04 0.06 0.02 0.05 0.05 0.08 SEQID-01382P36010 — — 1 0.50 0.21 0.04 0.07 0.03 0.06 0.01 0.04 0.08 0.05 0.02 0.060.08 0.10 SEQID-01383 Q02753 — — 0 0.46 0.19 0.04 0.12 0.04 0.02 0.010.06 0.06 0.04 0.05 0.05 0.05 0.12 SEQID-01384 P40159 — — 1 0.24 0.050.04 0.05 0.14 0.02 0.00 0.14 0.06 0.16 0.03 0.02 0.02 0.03 SEQID-01385P05755 — — 0 0.41 0.20 0.06 0.17 0.02 0.05 0.00 0.03 0.10 0.03 0.02 0.050.10 0.10 SEQID-01386 P08067 — — 1 0.49 0.21 0.05 0.06 0.03 0.07 0.020.03 0.04 0.04 0.03 0.06 0.08 0.08 SEQID-01387 Q04432 — — 1 0.51 0.200.07 0.02 0.04 0.10 0.00 0.01 0.06 0.05 0.03 0.05 0.07 0.11 SEQID-01388P39015 — — 1 0.36 0.12 0.08 0.10 0.12 0.08 0.00 0.04 0.08 0.02 0.00 0.020.05 0.14 SEQID-01389 P36060 — — 1 0.52 0.19 0.03 0.03 0.05 0.07 0.000.05 0.06 0.03 0.04 0.05 0.09 0.12 SEQID-01390 P53228 — — 1 0.49 0.210.06 0.05 0.03 0.06 0.01 0.03 0.11 0.02 0.03 0.06 0.09 0.12 SEQID-01391P43567 — — 1 0.51 0.24 0.06 0.05 0.04 0.06 0.01 0.03 0.05 0.04 0.03 0.060.10 0.08 SEQID-01392 P41338 — — 1 0.46 0.24 0.09 0.04 0.05 0.05 0.010.05 0.07 0.05 0.02 0.07 0.08 0.09 SEQID-01393 P54839 — — 1 0.47 0.210.04 0.05 0.06 0.07 0.01 0.05 0.05 0.04 0.02 0.06 0.09 0.10 SEQID-01394Q04792 — — 1 0.49 0.20 0.04 0.05 0.05 0.05 0.01 0.04 0.09 0.03 0.05 0.050.10 0.08 SEQID-01395 Q01574 — — 1 0.48 0.21 0.05 0.06 0.03 0.07 0.010.04 0.06 0.04 0.03 0.06 0.08 0.08 SEQID-01396 P25694 — — 1 0.43 0.220.06 0.09 0.05 0.09 0.00 0.03 0.10 0.04 0.02 0.06 0.08 0.07 SEQID-01397Q05050 — — 1 0.44 0.17 0.06 0.05 0.06 0.06 0.00 0.05 0.13 0.02 0.02 0.050.07 0.14 SEQID-01398 P38427 — — 1 0.45 0.21 0.04 0.06 0.06 0.06 0.010.06 0.06 0.02 0.03 0.07 0.09 0.07 SEQID-01399 P07259 — — 1 0.47 0.240.05 0.07 0.05 0.06 0.01 0.03 0.08 0.03 0.02 0.07 0.09 0.07 SEQID-01400P01097 — — 0 0.39 0.14 0.04 0.17 0.01 0.05 0.00 0.08 0.12 0.03 0.01 0.020.09 0.10 SEQID-01401 Q01519 — — 1 0.45 0.11 0.04 0.03 0.06 0.11 0.040.08 0.05 0.02 0.04 0.03 0.03 0.09 SEQID-01402 P38804 — — 0 0.47 0.200.05 0.03 0.07 0.04 0.00 0.02 0.14 0.06 0.00 0.05 0.08 0.13 SEQID-01403P53221 — — 0 0.48 0.24 0.05 0.13 0.02 0.06 0.00 0.05 0.05 0.03 0.02 0.050.11 0.16 SEQID-01404 P14127 — — 0 0.43 0.22 0.03 0.17 0.05 0.05 0.010.06 0.06 0.02 0.01 0.05 0.11 0.11 SEQID-01405 P04037 — — 1 0.46 0.220.03 0.07 0.03 0.07 0.02 0.04 0.07 0.04 0.03 0.05 0.11 0.07 SEQID-01406P00427 — — 0 0.39 0.19 0.06 0.13 0.05 0.06 0.01 0.03 0.12 0.01 0.02 0.030.10 0.07 SEQID-01407 P53849 — — 0 0.36 0.09 0.02 0.07 0.06 0.05 0.130.05 0.07 0.04 0.06 0.03 0.03 0.10 SEQID-01408 P04449 — — 1 0.49 0.130.07 0.14 0.03 0.02 0.00 0.05 0.07 0.03 0.02 0.04 0.04 0.22 SEQID-01409P38013 — — 1 0.51 0.22 0.06 0.01 0.04 0.07 0.02 0.03 0.07 0.03 0.02 0.070.05 0.09 SEQID-01410 P05740 — — 1 0.40 0.16 0.10 0.14 0.04 0.01 0.000.07 0.07 0.03 0.03 0.04 0.06 0.11 SEQID-01411 P0CX50 — — 0 0.50 0.200.07 0.17 0.03 0.03 0.01 0.02 0.03 0.04 0.03 0.04 0.08 0.12 SEQID-01412P05738 — — 0 0.54 0.27 0.02 0.08 0.07 0.06 0.00 0.04 0.05 0.03 0.03 0.090.05 0.12 SEQID-01413 P00447 — — 1 0.50 0.20 0.07 0.03 0.07 0.05 0.000.06 0.06 0.04 0.03 0.05 0.10 0.09 SEQID-01414 P0CX38 — — 0 0.44 0.200.05 0.16 0.03 0.05 0.00 0.06 0.08 0.04 0.01 0.05 0.08 0.13 SEQID-01415Q06146 — — 0 0.33 0.15 0.03 0.09 0.07 0.08 0.00 0.05 0.14 0.02 0.02 0.050.08 0.09 SEQID-01416 P38715 — — 1 0.52 0.24 0.03 0.04 0.04 0.06 0.020.04 0.08 0.03 0.04 0.07 0.11 0.10 SEQID-01417 P40531 — — 0 0.42 0.180.06 0.05 0.05 0.05 0.01 0.07 0.13 0.01 0.01 0.04 0.10 0.09 SEQID-01418P28834 — — 1 0.51 0.24 0.05 0.07 0.06 0.05 0.00 0.03 0.07 0.05 0.03 0.090.08 0.08 SEQID-01419 P41940 — — 1 0.54 0.28 0.03 0.04 0.05 0.06 0.010.02 0.08 0.04 0.02 0.09 0.10 0.10 SEQID-01420 P28241 — — 1 0.48 0.250.05 0.07 0.06 0.04 0.01 0.02 0.06 0.04 0.02 0.08 0.10 0.06 SEQID-01421P39714 — — 1 0.53 0.24 0.04 0.03 0.03 0.06 0.03 0.03 0.08 0.05 0.06 0.080.07 0.10 SEQID-01422 Q12443 — — 1 0.47 0.20 0.03 0.07 0.08 0.05 0.000.04 0.07 0.02 0.04 0.06 0.08 0.09 SEQID-01423 P07267 — — 1 0.47 0.210.05 0.02 0.05 0.07 0.01 0.03 0.08 0.05 0.03 0.06 0.10 0.07 SEQID-01424P36008 — — 1 0.48 0.19 0.07 0.05 0.05 0.07 0.00 0.02 0.08 0.02 0.01 0.040.09 0.12 SEQID-01425 Q04409 — — 1 0.47 0.24 0.03 0.08 0.04 0.05 0.020.03 0.09 0.04 0.03 0.06 0.12 0.06 SEQID-01426 P50095 — — 1 0.48 0.230.05 0.06 0.06 0.05 0.01 0.05 0.06 0.05 0.02 0.06 0.10 0.07 SEQID-01427P32316 — — 1 0.48 0.21 0.05 0.07 0.06 0.07 0.01 0.03 0.07 0.03 0.05 0.060.08 0.07 SEQID-01428 P37302 — — 1 0.45 0.19 0.05 0.03 0.08 0.07 0.010.04 0.08 0.03 0.04 0.06 0.08 0.09 SEQID-01429 Q03104 — — 1 0.50 0.170.03 0.03 0.06 0.10 0.00 0.06 0.04 0.02 0.02 0.03 0.09 0.13 SEQID-01430P15705 — — 1 0.39 0.14 0.08 0.06 0.06 0.07 0.00 0.06 0.11 0.02 0.02 0.050.07 0.12 SEQID-01431 Q00711 — — 1 0.46 0.19 0.06 0.09 0.04 0.06 0.020.03 0.07 0.05 0.05 0.05 0.08 0.06 SEQID-01432 P07244 — — 1 0.48 0.250.06 0.05 0.04 0.07 0.01 0.05 0.06 0.05 0.03 0.07 0.09 0.06 SEQID-01433P41058 — — 1 0.42 0.11 0.02 0.19 0.05 0.03 0.06 0.04 0.04 0.03 0.08 0.030.03 0.08 SEQID-01434 P02309 — — 0 0.47 0.23 0.04 0.19 0.01 0.03 0.000.02 0.05 0.08 0.02 0.07 0.09 0.12 SEQID-01435 P22803 — — 0 0.48 0.210.10 0.01 0.02 0.07 0.02 0.05 0.07 0.03 0.00 0.05 0.05 0.10 SEQID-01436P20081 — — 1 0.48 0.25 0.02 0.05 0.05 0.07 0.01 0.03 0.05 0.08 0.01 0.080.07 0.07 SEQID-01437 Q04438 — — 1 0.36 0.13 0.02 0.11 0.07 0.08 0.000.07 0.09 0.03 0.03 0.03 0.04 0.08 SEQID-01438 P02294 — — 0 0.47 0.160.08 0.07 0.02 0.02 0.00 0.04 0.07 0.02 0.02 0.06 0.05 0.17 SEQID-01439P38701 — — 1 0.51 0.25 0.02 0.07 0.05 0.02 0.00 0.10 0.11 0.02 0.02 0.100.05 0.13 SEQID-01440 P38061 — — 1 0.55 0.19 0.06 0.12 0.05 0.02 0.000.02 0.03 0.03 0.07 0.06 0.07 0.16 SEQID-01441 P32445 — — 1 0.44 0.160.05 0.08 0.08 0.05 0.00 0.05 0.08 0.03 0.02 0.04 0.07 0.08 SEQID-01442P38754 — — 0 0.53 0.24 0.10 0.11 0.02 0.03 0.01 0.06 0.04 0.03 0.00 0.060.08 0.14 SEQID-01443 Q03048 — — 1 0.44 0.19 0.05 0.07 0.04 0.09 0.010.01 0.08 0.03 0.01 0.04 0.08 0.09 SEQID-01444 Q01855 — — 0 0.49 0.180.06 0.14 0.04 0.01 0.00 0.02 0.07 0.04 0.03 0.05 0.06 0.10 SEQID-01445P0CX54 — — 0 0.46 0.24 0.06 0.07 0.04 0.05 0.01 0.04 0.09 0.04 0.02 0.100.07 0.13 SEQID-01446 P40414 — — 0 0.36 0.16 0.03 0.04 0.08 0.05 0.010.08 0.25 0.00 0.00 0.02 0.12 0.14 SEQID-01447 Q3E757 — — 1 0.48 0.200.03 0.13 0.04 0.06 0.01 0.04 0.07 0.04 0.02 0.06 0.06 0.11 SEQID-01448Q12402 — — 1 0.54 0.27 0.05 0.04 0.03 0.03 0.00 0.04 0.04 0.03 0.01 0.080.13 0.07 SEQID-01449 Q96VH4 — — 1 0.49 0.19 0.09 0.04 0.04 0.04 0.000.05 0.07 0.03 0.03 0.08 0.06 0.09 SEQID-01450 P52286 — — 1 0.38 0.180.03 0.09 0.09 0.13 0.00 0.02 0.13 0.01 0.02 0.05 0.07 0.06 SEQID-01451P26785 — — 1 0.50 0.11 0.07 0.12 0.02 0.04 0.00 0.03 0.05 0.03 0.02 0.040.09 0.15 SEQID-01452 P32471 — — 1 0.44 0.17 0.10 0.01 0.03 0.11 0.000.05 0.13 0.02 0.02 0.06 0.06 0.10 SEQID-01453 P53184 — — 1 0.53 0.220.03 0.04 0.04 0.10 0.01 0.03 0.06 0.02 0.07 0.07 0.06 0.09 SEQID-01454P32835 — — 1 0.48 0.20 0.05 0.05 0.05 0.06 0.01 0.06 0.08 0.03 0.02 0.050.08 0.09 SEQID-01455 P17891 — — 1 0.38 0.14 0.05 0.06 0.05 0.16 0.000.06 0.14 0.02 0.01 0.05 0.06 0.11 SEQID-01456 P05626 — — 1 0.48 0.250.06 0.06 0.04 0.04 0.00 0.06 0.09 0.02 0.01 0.05 0.11 0.10 SEQID-01457P40106 — — 1 0.49 0.20 0.07 0.04 0.04 0.08 0.01 0.02 0.08 0.04 0.02 0.080.07 0.12 SEQID-01458 P27616 — — 1 0.50 0.23 0.04 0.05 0.03 0.07 0.000.03 0.10 0.03 0.02 0.07 0.09 0.11 SEQID-01459 P47143 — — 1 0.49 0.230.08 0.02 0.04 0.07 0.01 0.04 0.07 0.04 0.03 0.05 0.10 0.08 SEQID-01460P32449 — — 1 0.45 0.22 0.07 0.07 0.07 0.06 0.01 0.05 0.07 0.05 0.03 0.070.09 0.07 SEQID-01461 P13663 — — 1 0.48 0.26 0.06 0.06 0.03 0.06 0.020.04 0.08 0.04 0.03 0.09 0.10 0.09 SEQID-01462 P32771 — — 1 0.50 0.210.07 0.04 0.03 0.07 0.04 0.03 0.07 0.06 0.03 0.07 0.06 0.10 SEQID-01463P32288 — — 1 0.41 0.15 0.05 0.08 0.04 0.06 0.02 0.04 0.08 0.05 0.04 0.070.05 0.06 SEQID-01464 P09624 — — 1 0.51 0.24 0.06 0.05 0.05 0.05 0.010.03 0.09 0.05 0.04 0.08 0.08 0.11 SEQID-01465 Q05911 — — 1 0.49 0.230.06 0.09 0.04 0.06 0.01 0.04 0.09 0.02 0.03 0.06 0.10 0.06 SEQID-01466P54114 — — 1 0.50 0.21 0.06 0.03 0.05 0.07 0.01 0.04 0.07 0.04 0.01 0.070.08 0.11 SEQID-01467 P32582 — — 1 0.50 0.24 0.04 0.04 0.06 0.08 0.000.03 0.07 0.04 0.02 0.03 0.10 0.12 SEQID-01468 P15891 — — 1 0.36 0.140.06 0.04 0.05 0.08 0.00 0.04 0.15 0.02 0.01 0.05 0.05 0.12 SEQID-01469P53051 — — 1 0.46 0.15 0.03 0.06 0.06 0.07 0.01 0.02 0.09 0.03 0.03 0.050.06 0.09 SEQID-01470 P09232 — — 1 0.47 0.18 0.05 0.04 0.06 0.09 0.010.04 0.08 0.05 0.05 0.06 0.07 0.11 SEQID-01471 P52910 — — 1 0.47 0.220.05 0.06 0.04 0.06 0.01 0.03 0.07 0.04 0.04 0.06 0.07 0.07 SEQID-01472P07264 — — 1 0.47 0.20 0.05 0.06 0.04 0.07 0.01 0.04 0.03 0.04 0.03 0.070.08 0.09 SEQID-01473 P33416 — — 1 0.47 0.25 0.05 0.10 0.04 0.08 0.010.04 0.09 0.03 0.02 0.07 0.11 0.10 SEQID-01474 P21306 — — 0 0.40 0.150.12 0.07 0.05 0.02 0.00 0.08 0.04 0.02 0.00 0.05 0.07 0.08 SEQID-01475P01095 — — 0 0.63 0.25 0.02 0.00 0.08 0.08 0.00 0.00 0.11 0.02 0.10 0.030.07 0.16 SEQID-01476 P0CX26 — — 1 0.46 0.16 0.08 0.15 0.00 0.01 0.050.04 0.04 0.05 0.01 0.04 0.03 0.14 SEQID-01477 P14120 — — 0 0.52 0.280.05 0.04 0.04 0.02 0.00 0.04 0.06 0.04 0.00 0.07 0.13 0.13 SEQID-01478P25373 — — 0 0.47 0.27 0.05 0.04 0.07 0.05 0.02 0.05 0.13 0.03 0.03 0.080.13 0.08 SEQID-01479 Q3E792 — — 0 0.50 0.21 0.08 0.09 0.00 0.04 0.000.05 0.05 0.02 0.03 0.08 0.08 0.19 SEQID-01480 P40037 — — 0 0.47 0.250.10 0.03 0.08 0.05 0.01 0.03 0.07 0.01 0.03 0.07 0.07 0.06 SEQID-01481P32463 — — 0 0.41 0.23 0.05 0.09 0.06 0.10 0.01 0.05 0.06 0.01 0.01 0.090.06 0.06 SEQID-01482 P00128 — — 1 0.44 0.24 0.06 0.03 0.04 0.06 0.010.04 0.11 0.01 0.03 0.09 0.12 0.08 SEQID-01483 P07281 — — 1 0.39 0.200.06 0.12 0.04 0.06 0.00 0.06 0.07 0.05 0.02 0.07 0.06 0.09 SEQID-01484P04456 — — 0 0.51 0.22 0.09 0.07 0.05 0.04 0.00 0.02 0.04 0.02 0.01 0.050.08 0.18 SEQID-01485 Q12513 — — 0 0.39 0.20 0.04 0.07 0.09 0.11 0.010.03 0.12 0.03 0.02 0.08 0.07 0.08 SEQID-01486 P05756 — — 1 0.46 0.240.06 0.13 0.04 0.03 0.00 0.02 0.05 0.03 0.03 0.09 0.09 0.10 SEQID-01487P39726 — — 1 0.46 0.21 0.04 0.04 0.05 0.05 0.00 0.05 0.12 0.04 0.02 0.040.10 0.06 SEQID-01488 Q12408 — — 0 0.45 0.28 0.04 0.04 0.06 0.05 0.020.02 0.12 0.04 0.01 0.09 0.11 0.05 SEQID-01489 P40043 — — 1 0.56 0.160.02 0.02 0.02 0.08 0.01 0.03 0.13 0.02 0.10 0.04 0.05 0.13 SEQID-01490P38886 — — 0 0.41 0.20 0.05 0.07 0.06 0.06 0.00 0.10 0.11 0.03 0.03 0.060.09 0.04 SEQID-01491 Q07651 — — 1 0.49 0.19 0.06 0.06 0.06 0.03 0.020.03 0.02 0.04 0.01 0.03 0.11 0.05 SEQID-01492 Q07551 — — 1 0.48 0.220.04 0.04 0.04 0.05 0.00 0.06 0.09 0.02 0.02 0.07 0.10 0.10 SEQID-01493P50107 — — 1 0.47 0.17 0.02 0.05 0.06 0.06 0.02 0.03 0.09 0.04 0.05 0.050.08 0.10 SEQID-01494 P04173 — — 1 0.50 0.26 0.07 0.04 0.04 0.07 0.010.03 0.08 0.04 0.02 0.07 0.12 0.09 SEQID-01495 P49723 — — 1 0.49 0.170.05 0.04 0.06 0.06 0.01 0.03 0.11 0.02 0.02 0.07 0.07 0.11 SEQID-01496P40495 — — 0 0.45 0.25 0.06 0.08 0.04 0.06 0.01 0.05 0.07 0.05 0.01 0.080.09 0.08 SEQID-01497 P08524 — — 1 0.48 0.22 0.05 0.04 0.04 0.07 0.020.04 0.10 0.02 0.02 0.06 0.10 0.11 SEQID-01498 Q12123 — — 1 0.50 0.230.02 0.07 0.05 0.07 0.00 0.03 0.07 0.03 0.05 0.08 0.09 0.08 SEQID-01499Q12329 — — 0 0.34 0.14 0.03 0.07 0.06 0.06 0.00 0.06 0.13 0.03 0.04 0.040.06 0.07 SEQID-01500 P38219 — — 1 0.49 0.24 0.05 0.07 0.04 0.06 0.010.04 0.10 0.03 0.02 0.09 0.09 0.11 SEQID-01501 P38891 — — 1 0.49 0.210.05 0.06 0.05 0.04 0.01 0.04 0.07 0.04 0.02 0.05 0.10 0.08 SEQID-01502P09938 — — 1 0.50 0.19 0.05 0.05 0.06 0.06 0.00 0.02 0.13 0.02 0.03 0.060.09 0.10 SEQID-01503 P07991 — — 1 0.51 0.24 0.07 0.04 0.03 0.05 0.020.04 0.07 0.04 0.06 0.07 0.11 0.08 SEQID-01504 P29952 — — 1 0.46 0.190.05 0.05 0.05 0.07 0.01 0.05 0.08 0.03 0.03 0.06 0.08 0.10 SEQID-01505P40054 — — 1 0.47 0.26 0.05 0.04 0.07 0.04 0.01 0.06 0.07 0.03 0.03 0.090.10 0.06 SEQID-01506 P32481 — — 1 0.48 0.25 0.05 0.07 0.04 0.06 0.020.05 0.10 0.04 0.02 0.10 0.08 0.09 SEQID-01507 P03536 — — 1 0.45 0.240.04 0.09 0.04 0.07 0.00 0.05 0.07 0.03 0.03 0.08 0.10 0.05 SEQID-01508P06208 — — 1 0.42 0.20 0.06 0.08 0.06 0.06 0.01 0.04 0.08 0.03 0.02 0.060.07 0.07 SEQID-01509 P46655 — — 1 0.50 0.21 0.05 0.07 0.05 0.09 0.010.03 0.07 0.03 0.02 0.07 0.08 0.11 SEQID-01510 P04801 — — 1 0.48 0.180.03 0.07 0.04 0.06 0.01 0.04 0.10 0.03 0.03 0.05 0.08 0.10 SEQID-01511P00915 — — 1 0.47 0.24 0.05 0.04 0.04 0.06 0.01 0.05 0.10 0.03 0.02 0.060.11 0.09 SEQID-01512 P39730 — — 1 0.45 0.20 0.05 0.06 0.03 0.06 0.010.06 0.14 0.03 0.01 0.05 0.09 0.14 SEQID-01513 P22515 — — 1 0.48 0.220.04 0.05 0.06 0.08 0.01 0.04 0.08 0.03 0.02 0.06 0.10 0.09 SEQID-01514Q00955 — — 1 0.47 0.22 0.04 0.08 0.05 0.06 0.00 0.04 0.09 0.03 0.03 0.070.09 0.07 SEQID-01515 P37299 — — 1 0.56 0.20 0.03 0.04 0.03 0.04 0.000.01 0.05 0.05 0.05 0.01 0.17 0.07 SEQID-01516 P50263 — — 0 0.45 0.030.03 0.04 0.12 0.10 0.00 0.06 0.06 0.06 0.05 0.01 0.01 0.16 SEQID-01517P01098 — — 0 0.37 0.18 0.04 0.14 0.09 0.03 0.01 0.06 0.10 0.03 0.03 0.060.10 0.11 SEQID-01518 Q12497 — — 0 0.42 0.12 0.03 0.13 0.05 0.10 0.000.06 0.07 0.03 0.03 0.02 0.08 0.13 SEQID-01519 P05745 — — 0 0.49 0.200.07 0.17 0.05 0.01 0.00 0.00 0.06 0.04 0.01 0.08 0.06 0.16 SEQID-01520Q3E841 — — 0 0.47 0.24 0.05 0.06 0.06 0.03 0.00 0.01 0.08 0.04 0.03 0.090.06 0.10 SEQID-01521 P38910 — — 0 0.51 0.29 0.06 0.04 0.05 0.07 0.000.07 0.06 0.04 0.00 0.07 0.11 0.12 SEQID-01522 P41056 — — 1 0.46 0.200.05 0.14 0.07 0.00 0.00 0.03 0.04 0.04 0.03 0.06 0.06 0.09 SEQID-01523P39939 — — 0 0.37 0.16 0.08 0.19 0.07 0.03 0.03 0.01 0.04 0.01 0.03 0.050.03 0.14 SEQID-01524 Q08245 — — 0 0.42 0.14 0.08 0.01 0.07 0.03 0.000.11 0.21 0.02 0.00 0.04 0.04 0.20 SEQID-01525 P04912 — — 0 0.42 0.240.10 0.11 0.07 0.02 0.00 0.05 0.05 0.06 0.03 0.06 0.14 0.10 SEQID-01526P0CX41 — — 0 0.45 0.22 0.07 0.11 0.06 0.04 0.01 0.02 0.04 0.07 0.00 0.050.07 0.10 SEQID-01527 P07274 — — 1 0.43 0.24 0.06 0.06 0.03 0.07 0.010.09 0.05 0.06 0.03 0.08 0.07 0.05 SEQID-01528 Q12305 — — 1 0.43 0.180.04 0.04 0.06 0.07 0.01 0.03 0.07 0.04 0.04 0.06 0.05 0.08 SEQID-01529P40185 — — 0 0.48 0.23 0.07 0.05 0.09 0.03 0.01 0.04 0.06 0.01 0.03 0.040.08 0.08 SEQID-01530 P38879 — — 0 0.41 0.21 0.09 0.03 0.09 0.07 0.000.08 0.10 0.03 0.01 0.07 0.06 0.11 SEQID-01531 P11076 — — 1 0.49 0.220.04 0.09 0.07 0.04 0.01 0.03 0.09 0.04 0.01 0.06 0.10 0.06 SEQID-01532P49435 — — 0 0.50 0.26 0.07 0.03 0.04 0.04 0.01 0.04 0.11 0.04 0.01 0.070.14 0.09 SEQID-01533 P22141 — — 0 0.45 0.23 0.03 0.08 0.02 0.09 0.000.07 0.06 0.03 0.02 0.07 0.10 0.08 SEQID-01534 P07260 — — 1 0.52 0.200.03 0.05 0.04 0.08 0.00 0.03 0.10 0.03 0.04 0.05 0.09 0.10 SEQID-01535Q04304 — — 1 0.46 0.25 0.06 0.06 0.06 0.06 0.01 0.03 0.08 0.03 0.01 0.070.09 0.09 SEQID-01536 Q01976 — — 1 0.48 0.23 0.03 0.07 0.04 0.07 0.020.05 0.09 0.03 0.02 0.08 0.08 0.10 SEQID-01537 Q12522 — — 0 0.43 0.270.04 0.08 0.06 0.05 0.02 0.06 0.09 0.04 0.02 0.07 0.11 0.01 SEQID-01538P40582 — — 1 0.48 0.22 0.05 0.05 0.03 0.06 0.00 0.04 0.08 0.02 0.04 0.070.11 0.09 SEQID-01539 P39929 — — 1 0.44 0.20 0.04 0.05 0.08 0.06 0.000.06 0.17 0.02 0.02 0.06 0.09 0.10 SEQID-01540 P39931 — — 1 0.51 0.200.03 0.05 0.04 0.03 0.00 0.02 0.15 0.03 0.08 0.07 0.08 0.09 SEQID-01541P00410 — — 1 0.53 0.28 0.04 0.03 0.03 0.06 0.01 0.04 0.07 0.02 0.02 0.100.11 0.04 SEQID-01542 P15873 — — 0 0.51 0.26 0.03 0.04 0.02 0.11 0.010.04 0.08 0.02 0.01 0.09 0.13 0.08 SEQID-01543 P32379 — — 1 0.43 0.220.06 0.06 0.03 0.06 0.01 0.03 0.15 0.04 0.03 0.06 0.11 0.07 SEQID-01544P21801 — — 1 0.46 0.19 0.04 0.03 0.05 0.05 0.05 0.06 0.04 0.02 0.02 0.050.11 0.09 SEQID-01545 P30656 — — 1 0.45 0.20 0.06 0.06 0.04 0.06 0.020.05 0.06 0.05 0.03 0.06 0.08 0.06 SEQID-01546 Q04491 — — 1 0.51 0.230.05 0.04 0.04 0.06 0.01 0.03 0.09 0.04 0.05 0.05 0.08 0.08 SEQID-01547P07143 — — 1 0.43 0.16 0.08 0.07 0.04 0.05 0.01 0.03 0.07 0.04 0.03 0.030.08 0.07 SEQID-01548 P24280 — — 1 0.44 0.18 0.04 0.06 0.03 0.06 0.010.04 0.10 0.03 0.02 0.05 0.09 0.09 SEQID-01549 P01120 — — 0 0.37 0.170.05 0.06 0.11 0.06 0.01 0.08 0.07 0.05 0.01 0.05 0.06 0.08 SEQID-01550P14065 — — 1 0.51 0.24 0.04 0.04 0.06 0.06 0.01 0.05 0.07 0.03 0.04 0.070.10 0.10 SEQID-01551 P53598 — — 0 0.51 0.22 0.06 0.04 0.02 0.04 0.010.07 0.07 0.06 0.02 0.10 0.07 0.10 SEQID-01552 P47120 — — 1 0.43 0.220.03 0.06 0.05 0.07 0.01 0.04 0.12 0.02 0.03 0.04 0.11 0.07 SEQID-01553Q12068 — — 1 0.51 0.22 0.05 0.04 0.05 0.08 0.01 0.03 0.08 0.03 0.03 0.060.09 0.11 SEQID-01554 P38115 — — 1 0.49 0.24 0.04 0.05 0.05 0.06 0.010.02 0.10 0.03 0.04 0.07 0.12 0.09 SEQID-01555 P53839 — — 1 0.49 0.240.04 0.07 0.05 0.05 0.01 0.04 0.11 0.04 0.04 0.06 0.10 0.08 SEQID-01556P32366 — — 1 0.43 0.21 0.04 0.06 0.06 0.07 0.02 0.05 0.09 0.02 0.02 0.070.11 0.04 SEQID-01557 Q03102 — — 1 0.53 0.25 0.05 0.02 0.05 0.06 0.010.04 0.06 0.05 0.01 0.06 0.11 0.12 SEQID-01558 Q06151 — — 1 0.47 0.230.02 0.06 0.07 0.06 0.01 0.04 0.08 0.03 0.03 0.10 0.09 0.08 SEQID-01559P32628 — — 0 0.37 0.17 0.03 0.05 0.04 0.06 0.01 0.08 0.14 0.04 0.01 0.040.08 0.05 SEQID-01560 P23644 — — 1 0.45 0.21 0.05 0.04 0.06 0.05 0.010.09 0.05 0.04 0.01 0.04 0.11 0.06 SEQID-01561 P32377 — — 1 0.48 0.190.06 0.06 0.04 0.06 0.01 0.05 0.08 0.02 0.02 0.05 0.09 0.07 SEQID-01562P27476 — — 1 0.31 0.08 0.04 0.08 0.04 0.07 0.00 0.02 0.17 0.05 0.01 0.030.03 0.11 SEQID-01563 P36046 — — 1 0.32 0.10 0.04 0.05 0.08 0.09 0.020.06 0.17 0.03 0.02 0.02 0.04 0.11 SEQID-01564 P23542 — — 1 0.50 0.210.06 0.04 0.05 0.05 0.01 0.05 0.05 0.03 0.04 0.06 0.09 0.08 SEQID-01565Q08412 — — 1 0.35 0.14 0.03 0.09 0.06 0.10 0.00 0.06 0.15 0.02 0.03 0.030.06 0.08 SEQID-01566 P53549 — — 0 0.44 0.21 0.04 0.10 0.03 0.07 0.000.05 0.12 0.04 0.02 0.08 0.09 0.08 SEQID-01567 P19262 — — 1 0.48 0.200.06 0.07 0.04 0.04 0.00 0.03 0.11 0.03 0.01 0.05 0.08 0.11 SEQID-01568P02557 — — 1 0.43 0.18 0.04 0.06 0.06 0.07 0.01 0.06 0.09 0.04 0.03 0.050.07 0.04 SEQID-01569 P04076 — — 1 0.49 0.22 0.04 0.08 0.03 0.08 0.010.04 0.08 0.04 0.03 0.05 0.12 0.07 SEQID-01570 P07284 — — 1 0.45 0.190.03 0.05 0.05 0.05 0.02 0.05 0.12 0.03 0.02 0.06 0.09 0.12 SEQID-01571P17649 — — 1 0.45 0.19 0.06 0.05 0.04 0.07 0.02 0.05 0.08 0.03 0.03 0.060.09 0.10 SEQID-01572 P08417 — — 1 0.49 0.22 0.06 0.04 0.07 0.03 0.020.06 0.08 0.04 0.04 0.06 0.10 0.08 SEQID-01573 P16130 — — 1 0.49 0.210.05 0.04 0.06 0.06 0.00 0.04 0.08 0.03 0.01 0.07 0.09 0.10 SEQID-01574P14904 — — 1 0.49 0.22 0.04 0.05 0.06 0.06 0.01 0.03 0.09 0.04 0.03 0.060.10 0.09 SEQID-01575 P38625 — — 1 0.52 0.24 0.04 0.05 0.04 0.06 0.010.04 0.08 0.04 0.04 0.08 0.09 0.08 SEQID-01576 P30952 — — 1 0.49 0.220.04 0.06 0.07 0.06 0.01 0.04 0.07 0.03 0.03 0.07 0.10 0.07 SEQID-01577P32891 — — 1 0.49 0.21 0.04 0.06 0.05 0.08 0.02 0.02 0.07 0.03 0.03 0.060.09 0.10 SEQID-01578 P38695 — — 1 0.50 0.21 0.03 0.06 0.04 0.03 0.020.03 0.06 0.05 0.00 0.07 0.08 0.05 SEQID-01579 P15624 — — 1 0.48 0.220.04 0.06 0.05 0.07 0.01 0.03 0.09 0.02 0.03 0.07 0.09 0.09 SEQID-01580P32590 — — 1 0.47 0.20 0.05 0.07 0.05 0.03 0.01 0.03 0.09 0.02 0.02 0.060.08 0.10 SEQID-01581 P32775 — — 1 0.47 0.18 0.04 0.07 0.05 0.07 0.000.02 0.07 0.03 0.05 0.04 0.09 0.06 SEQID-01582 P53278 — — 1 0.40 0.150.04 0.05 0.07 0.06 0.00 0.09 0.15 0.01 0.02 0.04 0.07 0.12 SEQID-01583P13188 — — 1 0.47 0.19 0.02 0.08 0.05 0.06 0.01 0.03 0.10 0.03 0.02 0.050.07 0.11 SEQID-01584 P07245 — — 1 0.48 0.24 0.06 0.06 0.05 0.06 0.010.04 0.07 0.04 0.03 0.08 0.09 0.07 SEQID-01585 P40825 — — 1 0.48 0.200.04 0.05 0.05 0.08 0.01 0.03 0.09 0.04 0.02 0.06 0.09 0.11 SEQID-01586P20967 — — 1 0.47 0.19 0.04 0.07 0.04 0.05 0.01 0.05 0.08 0.03 0.04 0.050.10 0.08 SEQID-01587 P22855 — — 1 0.48 0.19 0.03 0.06 0.05 0.06 0.010.05 0.07 0.03 0.03 0.06 0.08 0.09 SEQID-01588 F0TEP7 — — 1 0.50 0.250.06 0.05 0.04 0.08 0.00 0.03 0.08 0.05 0.02 0.08 0.08 0.10 SEQID-01589F0TIG2 — — 1 0.46 0.22 0.04 0.09 0.04 0.08 0.01 0.04 0.08 0.04 0.02 0.080.08 0.09 SEQID-01590 F0TIH2 — — 1 0.47 0.20 0.05 0.11 0.05 0.05 0.000.04 0.05 0.06 0.05 0.09 0.07 0.13 SEQID-01591 F0TE83 — — 1 0.50 0.210.07 0.04 0.06 0.07 0.01 0.03 0.06 0.04 0.03 0.06 0.07 0.08 SEQID-01592F0TEJ0 — — 0 0.45 0.21 0.05 0.05 0.06 0.08 0.01 0.02 0.11 0.05 0.03 0.070.08 0.08 SEQID-01593 F0TDZ2 — — 0 0.49 0.23 0.05 0.06 0.02 0.08 0.000.04 0.10 0.05 0.04 0.07 0.08 0.07 SEQID-01594 F0TEQ7 — — 0 0.45 0.240.03 0.08 0.06 0.10 0.00 0.03 0.09 0.04 0.02 0.06 0.08 0.10 SEQID-01595F0TFN9 — — 1 0.48 0.22 0.05 0.06 0.04 0.10 0.00 0.06 0.08 0.03 0.01 0.070.07 0.08 SEQID-01596 F0TGC0 — — 1 0.49 0.15 0.08 0.16 0.04 0.04 0.000.04 0.02 0.03 0.02 0.04 0.07 0.16 SEQID-01597 F0TIP0 — — 1 0.48 0.220.07 0.05 0.04 0.09 0.00 0.06 0.04 0.04 0.01 0.05 0.08 0.11 SEQID-01598F0THG83 — — 1 0.48 0.21 0.03 0.09 0.03 0.07 0.01 0.03 0.11 0.03 0.040.07 0.10 0.09 SEQID-01599 F0THR9 — — 1 0.45 0.20 0.05 0.07 0.05 0.080.01 0.04 0.06 0.04 0.03 0.07 0.07 0.08 SEQID-01600 F0TID9 — — 1 0.500.24 0.06 0.04 0.03 0.09 0.00 0.04 0.08 0.05 0.04 0.08 0.07 0.09SEQID-01601 F0TII4 — — 0 0.46 0.20 0.04 0.08 0.03 0.05 0.00 0.03 0.090.06 0.01 0.06 0.05 0.13 SEQID-01602 F0TEP6 — — 0 0.48 0.22 0.07 0.070.04 0.09 0.01 0.02 0.06 0.06 0.05 0.08 0.07 0.07 SEQID-01603 F0TFM5 — —1 0.46 0.20 0.05 0.08 0.07 0.07 0.00 0.06 0.08 0.03 0.03 0.06 0.06 0.14SEQID-01604 F0TI54 — — 1 0.50 0.19 0.09 0.02 0.08 0.06 0.00 0.02 0.030.04 0.01 0.02 0.06 0.12 SEQID-01605 F0TIG5 — — 0 0.44 0.19 0.04 0.140.05 0.03 0.00 0.03 0.09 0.05 0.04 0.04 0.07 0.12 SEQID-01606 F0TIG7 — —1 0.47 0.20 0.06 0.07 0.03 0.08 0.00 0.03 0.10 0.04 0.02 0.07 0.06 0.08SEQID-01607 F0TII6 — — 0 0.46 0.23 0.06 0.13 0.06 0.06 0.00 0.02 0.070.06 0.02 0.07 0.05 0.11 SEQID-01608 F0TIG9 — — 1 0.52 0.23 0.03 0.080.04 0.04 0.00 0.03 0.07 0.06 0.03 0.06 0.04 0.14 SEQID-01609 F0TIH5 — —1 0.44 0.20 0.07 0.14 0.05 0.05 0.00 0.05 0.08 0.05 0.02 0.08 0.06 0.10SEQID-01610 F0TDX9 — — 1 0.45 0.22 0.04 0.09 0.05 0.08 0.00 0.04 0.090.04 0.02 0.07 0.09 0.07 SEQID-01611 F0TE85 — — 1 0.44 0.20 0.06 0.040.05 0.07 0.02 0.03 0.12 0.04 0.02 0.07 0.07 0.10 SEQID-01612 F0TFK9 — —0 0.50 0.25 0.05 0.03 0.06 0.04 0.01 0.01 0.10 0.05 0.01 0.09 0.09 0.10SEQID-01613 F0TGI4 — — 1 0.46 0.20 0.07 0.05 0.05 0.08 0.01 0.03 0.110.05 0.02 0.07 0.08 0.10 SEQID-01614 F0TI74 — — 1 0.48 0.16 0.05 0.040.07 0.06 0.00 0.04 0.05 0.04 0.00 0.03 0.08 0.13 SEQID-01615 F0TI56 — —1 0.56 0.25 0.07 0.02 0.04 0.06 0.00 0.04 0.04 0.05 0.03 0.03 0.09 0.03SEQID-01616 F0TJ46 — — 1 0.43 0.17 0.05 0.03 0.11 0.04 0.00 0.05 0.030.04 0.01 0.06 0.04 0.09 SEQID-01617 F0TDQ0 — — 0 0.42 0.20 0.02 0.120.05 0.07 0.00 0.03 0.14 0.01 0.02 0.04 0.08 0.03 SEQID-01618 F0TDS8 — —1 0.41 0.20 0.03 0.15 0.04 0.04 0.00 0.06 0.09 0.04 0.03 0.04 0.10 0.07SEQID-01619 F0TE84 — — 1 0.52 0.24 0.06 0.03 0.05 0.09 0.00 0.01 0.070.05 0.03 0.08 0.09 0.12 SEQID-01620 F0TED5 — — 1 0.43 0.20 0.05 0.050.06 0.03 0.01 0.03 0.08 0.05 0.02 0.06 0.09 0.08 SEQID-01621 F0TEQ9 — —0 0.49 0.20 0.10 0.06 0.04 0.04 0.00 0.04 0.12 0.04 0.01 0.06 0.06 0.16SEQID-01622 F0TEU3 — — 1 0.44 0.21 0.05 0.07 0.05 0.06 0.01 0.08 0.070.03 0.02 0.08 0.08 0.08 SEQID-01623 F0TFQ7 — — 0 0.46 0.23 0.05 0.190.01 0.04 0.00 0.03 0.09 0.04 0.04 0.07 0.04 0.09 SEQID-01624 F0TFS5 — —1 0.49 0.17 0.05 0.03 0.07 0.05 0.00 0.04 0.04 0.04 0.01 0.05 0.06 0.14SEQID-01625 F0TGH0 — — 1 0.51 0.17 0.07 0.01 0.04 0.06 0.00 0.09 0.030.02 0.02 0.05 0.06 0.19 SEQID-01626 F0TH33 — — 1 0.52 0.23 0.08 0.030.05 0.06 0.00 0.01 0.06 0.06 0.03 0.10 0.08 0.09 SEQID-01627 F0THG4 — —1 0.48 0.20 0.05 0.09 0.03 0.05 0.00 0.04 0.11 0.03 0.05 0.06 0.08 0.07SEQID-01628 F0TIG8 — — 0 0.52 0.24 0.04 0.11 0.02 0.06 0.00 0.02 0.080.02 0.04 0.09 0.11 0.09 SEQID-01629 F0TIH8 — — 0 0.47 0.19 0.01 0.130.06 0.05 0.00 0.02 0.06 0.01 0.03 0.04 0.02 0.16 SEQID-01630 F0TIH9 — —0 0.48 0.27 0.05 0.13 0.04 0.06 0.01 0.02 0.07 0.06 0.01 0.09 0.06 0.11SEQID-01631 F0TII3 — — 1 0.46 0.26 0.05 0.09 0.06 0.06 0.00 0.02 0.070.04 0.01 0.12 0.06 0.11 SEQID-01632 F0TIJ3 — — 0 0.38 0.20 0.04 0.210.04 0.09 0.01 0.02 0.06 0.04 0.01 0.07 0.06 0.10 SEQID-01633 F0TIJ6 — —0 0.48 0.21 0.07 0.16 0.02 0.06 0.00 0.02 0.08 0.02 0.02 0.05 0.09 0.12SEQID-01634 F0TIR8 — — 1 0.50 0.23 0.08 0.05 0.03 0.08 0.01 0.04 0.060.04 0.05 0.10 0.07 0.09 SEQID-01635 F0TIS2 — — 1 0.44 0.22 0.08 0.050.06 0.09 0.01 0.03 0.06 0.05 0.02 0.06 0.09 0.07 SEQID-01636 F0TIU2 — —1 0.45 0.24 0.08 0.06 0.05 0.09 0.00 0.05 0.09 0.05 0.01 0.08 0.08 0.09SEQID-01637 F0TIX0 — — 0 0.40 0.18 0.07 0.00 0.08 0.19 0.01 0.04 0.110.03 0.01 0.03 0.08 0.13 SEQID-01638 P13538 — — 1 0.45 0.19 0.05 0.070.04 0.05 0.01 0.07 0.15 0.02 0.03 0.05 0.10 0.12 SEQID-01639 F1P3W7 — —1 0.45 0.19 0.05 0.07 0.04 0.05 0.01 0.07 0.15 0.02 0.02 0.05 0.10 0.12SEQID-01640 F1P3X4 — — 1 0.45 0.19 0.05 0.07 0.04 0.05 0.01 0.07 0.150.02 0.03 0.05 0.10 0.12 SEQID-01641 F1ND26 — — 1 0.45 0.19 0.06 0.070.04 0.05 0.01 0.07 0.15 0.02 0.02 0.05 0.10 0.12 SEQID-01642 F1NDL1 — —1 0.47 0.17 0.05 0.06 0.04 0.08 0.01 0.05 0.07 0.02 0.04 0.05 0.07 0.13SEQID-01643 F1NGF6 — — 1 0.47 0.20 0.04 0.07 0.03 0.05 0.01 0.04 0.110.03 0.03 0.06 0.06 0.09 SEQID-01644 P68139 — — 1 0.47 0.20 0.05 0.070.03 0.06 0.01 0.03 0.09 0.04 0.03 0.06 0.07 0.06 SEQID-01645 P00565 — —1 0.50 0.19 0.02 0.08 0.04 0.07 0.01 0.04 0.09 0.04 0.05 0.04 0.09 0.09SEQID-01646 P00548 — — 1 0.49 0.22 0.07 0.09 0.04 0.06 0.01 0.03 0.080.04 0.04 0.07 0.07 0.08 SEQID-01647 P16419 — — 1 0.45 0.20 0.04 0.090.03 0.06 0.01 0.03 0.11 0.03 0.02 0.04 0.07 0.09 SEQID-01648 Q5ZMQ2 — —1 0.47 0.20 0.05 0.07 0.02 0.06 0.01 0.04 0.09 0.04 0.03 0.08 0.07 0.06SEQID-01649 F1NU17 — — 1 0.54 0.24 0.06 0.03 0.04 0.07 0.02 0.02 0.070.05 0.03 0.05 0.09 0.13 SEQID-01650 P07322 — — 1 0.49 0.22 0.07 0.060.04 0.06 0.02 0.04 0.08 0.05 0.05 0.07 0.07 0.10 SEQID-01651 P20111 — —1 0.44 0.19 0.05 0.09 0.05 0.06 0.01 0.07 0.12 0.02 0.03 0.07 0.09 0.07SEQID-01652 P13585 — — 1 0.50 0.25 0.06 0.07 0.04 0.05 0.02 0.02 0.090.03 0.02 0.07 0.10 0.06 SEQID-01653 P00

56 — — 1 0.52 0.22 0.07 0.05 0.05 0.07 0.01 0.02 0.04 0.05 0.04 0.060.06 0.09 SEQID-01654 Q07734 — — 1 0.47 0.21 0.03 0.07 0.03 0.07 0.010.02 0.09 0.03 0.02 0.05 0.06 0.10 SEQID-01655 F1NN63 — — 1 0.47 0.200.06 0.08 0.05 0.07 0.01 0.03 0.05 0.05 0.03 0.08 0.07 0.08 SEQID-01656F2Z4L6 — — 1 0.43 0.18 0.04 0.06 0.03 0.07 0.05 0.06 0.09 0.02 0.03 0.060.07 0.09 SEQID-01657 F1NX83 — — 1 0.46 0.20 0.04 0.08 0.05 0.05 0.030.04 0.07 0.03 0.05 0.06 0.09 0.06 SEQID-01658 P00940 — — 1 0.51 0.230.07 0.04 0.03 0.06 0.02 0.04 0.083 0.06 0.04 0.07 0.07 0.11 SEQID-01659F1NXK1 — — 1 0.46 0.20 0.03 0.05 0.03 0.05 0.02 0.05 0.13 0.03 0.02 0.070.07 0.11 SEQID-01660 E1B5N7 — — 1 0.45 0.21 0.04 0.09 0.05 0.06 0.010.04 0.09 0.03 0.03 0.06 0.09 0.06 SEQID-01661 Q02173 — — 1 0.46 0.200.04 0.07 0.04 0.06 0.02 0.03 0.10 0.03 0.04 0.05 0.07 0.08 SEQID-01662F1NW35 — — 1 0.57 0.27 0.04 0.04 0.03 0.07 0.01 0.02 0.06 0.04 0.07 0.070.10 0.11 SEQID-01663 E19T53 — — 1 0.47 0.20 0.04 0.06 0.03 0.05 0.020.05 0.12 0.03 0.02 0.05 0.08 0.11 SEQID-01664 P02609 — — 1 0.48 0.170.05 0.05 0.05 0.09 0.01 0.03 0.11 0.04 0.01 0.07 0.05 0.11 SEQID-01665F1NIJ6 — — 1 0.55 0.21 0.05 0.05 0.05 0.05 0.01 0.03 0.07 0.04 0.06 0.060.10 0.09 SEQID-01666 P05031 — — 0 0.50 0.22 0.03 0.07 0.01 0.06 0.010.04 0.11 0.05 0.03 0.05 0.10 0.13 SEQID-01667 P68246 — — 1 0.45 0.170.05 0.11 0.03 0.07 0.01 0.05 0.14 0.02 0.03 0.02 0.11 0.16 SEQID-01668P11009 — — 1 0.45 0.21 0.04 0.11 0.04 0.07 0.02 0.03 0.07 0.04 0.03 0.040.10 0.07 SEQID-01669 P08106 — — 1 0.46 0.20 0.05 0.07 0.05 0.08 0.010.05 0.09 0.04 0.01 0.07 0.07 0.10 SEQID-01670 P02457 — — 1 0.24 0.090.08 0.08 0.03 0.05 0.01 0.04 0.07 0.16 0.01 0.02 0.04 0.05 SEQID-01671P02604 — — 0 0.46 0.17 0.09 0.03 0.05 0.06 0.00 0.04 0.13 0.03 0.01 0.050.07 0.12 SEQID-01672 Q52LN1 — — 1 0.45 0.20 0.06 0.10 0.04 0.06 0.010.04 0.09 0.03 0.03 0.06 0.09 0.07 SEQID-01673 Q05623 — — 1 0.42 0.160.07 0.06 0.03 0.05 0.01 0.04 0.10 0.02 0.03 0.05 0.05 0.10 SEQID-01674E1C3E2 — — 1 0.45 0.19 0.05 0.06 0.04 0.06 0.01 0.03 0.10 0.03 0.03 0.050.06 0.09 SEQID-01675 P51913 — — 1 0.46 0.23 0.06 0.06 0.06 0.07 0.010.03 0.08 0.04 0.02 0.06 0.09 0.10 SEQID-01676 O73885 — — 1 0.46 0.210.05 0.06 0.06 0.07 0.01 0.05 0.09 0.04 0.02 0.07 0.08 0.10 SEQID-01677P15989 — — 1 0.44 0.23 0.05 0.09 0.04 0.06 0.01 0.06 0.07 0.05 0.02 0.060.09 0.06 SEQID-01678 F1NCR0 — — 1 0.26 0.11 0.07 0.08 0.04 0.04 0.010.03 0.06 0.17 0.02 0.03 0.05 0.05 SEQID-01679 F1NKY4 — — 1 0.42 0.130.08 0.11 0.01 0.05 0.00 0.05 0.19 0.01 0.08 0.03 0.08 0.15 SEQID-01680P53449 — — 1 0.37 0.18 0.10 0.08 0.06 0.02 0.01 0.04 0.08 0.05 0.02 0.020.09 0.04 SEQID-01681 QS2MJ6 — — 1 0.51 0.22 0.07 0.08 0.02 0.06 0.010.05 0.03 0.05 0.01 0.08 0.07 0.10 SEQID-01682 P19204 — — 1 0.47 0.200.03 0.03 0.02 0.18 0.01 0.02 0.13 0.02 0.02 0.05 0.10 0.08 SEQID-01683F1N9H4 — — 1 0.50 0.21 0.05 0.06 0.04 0.05 0.01 0.03 0.08 0.05 0.03 0.080.06 0.12 SEQID-01684 E1BR47 — — 1 0.46 0.22 0.03 0.08 0.04 0.05 0.020.05 0.08 0.03 0.02 0.05 0.12 0.08 SEQID-01685 F1NY12 — — 0 0.49 0.220.05 0.05 0.03 0.06 0.01 0.03 0.07 0.05 0.02 0.06 0.10 0.11 SEQID-01686P02542 — — 1 0.38 0.18 0.06 0.13 0.04 0.05 0.00 0.09 0.13 0.02 0.02 0.040.09 0.05 SEQID-01687 F1NCJ4 — — 1 0.48 0.22 0.04 0.06 0.04 0.06 0.020.05 0.10 0.03 0.03 0.06 0.11 0.07 SEQID-01688 E1BVT3 — — 0 0.49 0.250.07 0.06 0.05 0.04 0.02 0.03 0.07 0.05 0.02 0.07 0.10 0.09 SEQID-01689E16XW3 — — 1 0.46 0.23 0.06 0.10 0.04 0.05 0.02 0.04 0.07 0.05 0.03 0.060.10 0.05 SEQID-01690 P79757 — — 1 0.43 0.17 0.04 0.09 0.03 0.04 0.010.04 0.11 0.02 0.03 0.06 0.06 0.09 SEQID-01691 P04268 — — 0 0.40 0.180.08 0.07 0.02 0.08 0.00 0.05 0.23 0.01 0.01 0.04 0.11 0.15 SEQID-01692P00508 — — 1 0.45 0.20 0.06 0.09 0.04 0.05 0.01 0.04 0.06 0.04 0.03 0.060.09 0.08 SEQID-01693 P09203 — — 1 0.43 0.17 0.04 0.07 0.05 0.06 0.020.06 0.09 0.04 0.03 0.04 0.07 0.04 SEQID-01694 F1NGA2 — — 0 0.45 0.250.07 0.10 0.03 0.05 0.00 0.06 0.07 0.05 0.01 0.07 0.10 0.06 SEQID-01695P15988 — — 1 0.38 0.17 0.04 0.09 0.03 0.07 0.02 0.05 0.08 0.08 0.01 0.060.07 0.07 SEQID-01696 F1NXK2 — — 0 0.49 0.23 0.04 0.11 0.02 0.08 0.000.00 0.09 0.04 0.00 0.08 0.08 0.07 SEQID-01697 F1P0E4 — — 1 0.50 0.180.05 0.03 0.06 0.06 0.01 0.02 0.05 0.06 0.01 0.04 0.09 0.11 SEQID-01698E1BU93 — — 1 0.46 0.15 0.03 0.06 0.04 0.04 0.00 0.03 0.08 0.06 0.05 0.040.08 0.10 SEQID-01699 P07341 — — 1 0.44 0.20 0.08 0.06 0.04 0.04 0.020.07 0.07 0.04 0.02 0.05 0.10 0.08 SEQID-01700 P17785 — — 1 0.45 0.210.05 0.083 0.04 0.08 0.01 0.04 0.09 0.03 0.01 0.07 0.10 0.11 SEQID-01701E1BR89 — — 1 0.48 0.19 0.06 0.08 0.02 0.02 0.02 0.04 0.06 0.04 0.01 0.050.09 0.07 SEQID-01702 F1NXR6 — — 1 0.44 0.20 0.05 0.07 0.04 0.06 0.020.04 0.09 0.04 0.04 0.06 0.07 0.05 SEQID-01703 F1P0N2 — — 1 0.46 0.180.04 0.08 0.04 0.05 0.01 0.05 0.08 0.02 0.04 0.05 0.09 0.07 SEQID-01704F1NPH8 — — 1 0.37 0.19 0.06 0.10 0.03 0.05 0.03 0.10 0.13 0.02 0.03 0.030.13 0.07 SEQID-01705 P04713 — — 1 0.44 0.21 0.07 0.09 0.04 0.05 0.020.03 0.07 0.05 0.02 0.04 0.08 0.06 SEQID-01706 K7UZT6 — — 1 0.45 0.220.06 0.08 0.04 0.05 0.01 0.05 0.09 0.05 0.02 0.04 0.10 0.06 SEQID-01707B4F832 — — 1 0.44 0.21 0.08 0.10 0.02 0.04 0.02 0.04 0.07 0.05 0.01 0.050.08 0.08 SEQID-01708 P11155 — — 1 0.45 0.21 0.07 0.8 0.04 0.05 0.020.05 0.09 0.05 0.02 0.04 0.09 0.06 SEQID-01709 Q43247 — — 1 0.52 0.230.06 0.05 0.04 0.07 0.01 0.02 0.07 0.05 0.02 0.06 0.06 0.10 SEQID-01710P04712 — — 1 0.43 0.22 0.04 0.07 0.04 0.06 0.01 0.04 0.08 0.03 0.03 0.060.11 0.07 SEQID-01711

6TEC1 — — 1 0.46 0.23 0.08 0.10 0.02 0.07 0.03 0.01 0.08 0.06 0.04 0.030.08 0.05 SEQID-01712 Q0QWI2 — — 1 0.46 0.23 0.07 0.10 0.02 0.06 0.030.01 0.08 0.06 0.04 0.03 0.08 0.05 SEQID-01713 B4F8M9 — — 1 0.54 0.180.04 0.10 0.02 0.04 0.01 0.04 0.07 0.04 0.05 0.05 0.06 0.15 SEQID-01714Q5K3Q7 — — 1 0.53 0.28 0.09 0.03 0.03 0.04 0.01 0.02 0.05 0.06 0.01 0.090.10 0.05 SEQID-01715 B4FJZ7 — — 1 0.46 0.14 0.07 0.18 0.02 0.02 0.000.03 0.07 0.02 0.03 0.04 0.06 0.18 SEQID-01716

6T1F1 — — 1 0.47 0.14 0.06 0.18 0.02 0.03 0.00 0.03 0.06 0.02 0.04 0.040.07 0.18 SEQID-01717 K7URL6 — — 1 0.53 0.28 0.09 0.03 0.03 0.04 0.010.02 0.05 0.06 0.01 0.09 0.10 0.05 SEQID-01718 B4FUW2 — — 1 0.42 0.170.03 0.22 0.04 0.02 0.01 0.05 0.04 0.04 0.04 0.03 0.07 0.10 SEQID-01719B6UEE8 — — 1 0.47 0.26 0.11 0.06 0.03 0.05 0.01 0.01 0.05 0.06 0.02 0.060.11 0.03 SEQID-01720 B4FUK7 — — 1 0.47 0.15 0.05 0.07 0.06 0.07 0.020.03 0.06 0.05 0.07 0.02 0.06 0.07 SEQID-01721

4FY16 — — 1 0.53 0.21 0.05 0.06 0.03 0.06 0.01 0.03 0.07 0.04 0.03 0.070.06 0.13 SEQID-01722 Q946V2 — — 1 0.41 0.20 0.06 0.08 0.04 0.05 0.010.08 0.06 0.05 0.05 0.04 0.09 0.03 SEQID-01723 B6T1H0 — — 0 0.44 0.170.04 0.17 0.04 0.06 0.01 0.05 0.05 0.04 0.00 0.04 0.08 0.15 SEQID-01724

4F989 — — 1 0.46 0.21 0.05 0.07 0.02 0.06 0.01 0.03 0.09 0.04 0.03 0.080.07 0.06 SEQID-01725 B4G1E1 — — 1 0.46 0.20 0.05 0.07 0.03 0.06 0.020.03 0.09 0.04 0.03 0.08 0.07 0.06 SEQID-01726 B6TQ68 — — 1 0.46 0.140.06 0.19 0.03 0.02 0.00 0.02 0.07 0.02 0.04 0.04 0.06 0.18 SEQID-01727B6SP93 — — 0 0.48 0.11 0.19 0.04 0.01 0.00 0.00 0.02 0.06 0.02 0.01 0.010.03 0.30 SEQID-01728 P

84

40 — — 1 0.45 0.22 0.07 0.06 0.04 0.05 0.02 0.03 0.09 0.04 0.02 0.050.11 0.10 SEQID-01729 B6TQ06 — — 1 0.47 0.21 0.05 0.07 0.02 0.06 0.010.03 0.08 0.04 0.03 0.08 0.07 0.06 SEQID-01730 B4FUH2 — — 1 0.44 0.210.07 0.09 0.04 0.04 0.01 0.05 0.06 0.04 0.03 0.05 0.10 0.04 SEQID-01731P21569 — — 1 0.49 0.17 0.05 0.06 0.05 0.04 0.02 0.03 0.07 0.07 0.02 0.030.04 0.09 SEQID-01732 P27923 — — 0 0.54 0.19 0.04 0.07 0.03 0.06 0.020.06 0.05 0.04 0.04 0.05 0.08 0.18 SEQID-01733 C0P455 — — 1 0.46 0.200.07 0.13 0.05 0.04 0.00 0.03 0.05 0.04 0.02 0.04 0.08 0.11 SEQID-01734C0PHE3 — — 1 0.47 0.23 0.03 0.10 0.03 0.08 0.01 0.07 0.07 0.04 0.02 0.060.10 0.05 SEQID-01735 B6SP74 — — 1 0.27 0.10 0.04 0.13 0.07 0.05 0.010.02 0.08 0.21 0.02 0.03 0.04 0.02 SEQID-01736 K7T5X3 — — 1 0.33 0.080.07 0.07 0.02 0.11 0.00 0.03 0.14 0.05 0.01 0.02 0.02 0.16 SEQID-01737K7V1U2 — — 1 0.44 0.18 0.06 0.06 0.03 0.09 0.01 0.04 0.14 0.03 0.01 0.050.06 0.15 SEQID-01738 B6T879 — — 0 0.50 0.16 0.09 0.05 0.02 0.02 0.000.02 0.09 0.03 0.02 0.06 0.05 0.22 SEQID-01738 Q946V3 — — 0 0.27 0.130.06 0.15 0.00 0.03 0.06 0.11 0.07 0.09 0.00 0.02 0.07 0.02 SEQID-01740P12863 — — 1 0.49 0.24 0.08 0.04 0.04 0.04 0.02 0.05 0.09 0.05 0.02 0.050.07 0.08 SEQID-01741 B6TC95 — — 0 0.47 0.08 0.19 0.04 0.02 0.01 0.000.01 0.05 0.01 0.01 0.01 0.04 0.31 SEQID-01742 P49106 — — 1 0.41 0.200.06 0.08 0.03 0.06 0.01 0.03 0.15 0.02 0.01 0.06 0.10 0.08 SEQID-01743B6U607 — — 1 0.04 0.23 0.09 0.09 0.05 0.04 0.01 0.04 0.09 0.05 0.02 0.020.12 0.06 SEQID-01744 C0P381 — — 0 0.30 0.11 0.02 0.02 0.03 0.01 0.050.37 0.05 0.02 0.11 0.03 0.05 0.02 SEQID-01745 B4G0K5 — — 1 0.45 0.150.04 0.07 0.06 0.07 0.02 0.04 0.06 0.06 0.06 0.03 0.05 0.06 SEQID-01746K7TNK3 — — 1 0.43 0.20 0.05 0.04 0.03 0.05 0.01 0.09 0.20 0.01 0.03 0.030.13 0.11 SEQID-01747 B6SGI4 — — 1 0.42 0.07 0.06 0.22 0.04 0.00 0.040.01 0.02 0.05 0.04 0.03 0.02 0.12 SEQID-01748 P04706 — — 0 0.37 0.210.05 0.04 0.00 0.00 0.07 0.16 0.01 0.03 0.09 0.02 0.12 0.00 SEQID-01749B6T5F2 — — 1 0.49 0.16 0.06 0.12 0.04 0.02 0.00 0.06 0.06 0.03 0.03 0.040.06 0.17 SEQID-01750 B6T440 — — 1 0.49 0.22 0.06 0.06 0.03 0.06 0.020.03 0.09 0.04 0.03 0.06 0.09 0.09 SEQID-01751 B6TN50 — — 1 0.47 0.190.06 0.06 0.05 0.07 0.01 0.03 0.09 0.03 0.02 0.05 0.09 0.14 SEQID-01752K7UDH4 — — 1 0.49 0.20 0.03 0.08 0.05 0.05 0.01 0.05 0.07 0.02 0.04 0.060.10 0.07 SEQID-01753 P62787 — — 0 0.47 0.22 0.04 0.21 0.02 0.03 0.000.02 0.05 0.09 0.02 0.07 0.08 0.11 SEQID-01754 B6SIA2 — — 0 0.33 0.130.08 0.22 0.03 0.04 0.05 0.03 0.04 0.04 0.05 0.04 0.01 0.09 SEQID-01755P01088 — — 1 0.38 0.22 0.09 0.11 0.01 0.03 0.06 0.02 0.06 0.05 0.02 0.060.12 0.02 SEQID-01756

4FK49 — — 1 0.50 0.22 0.05 0.06 0.03 0.05 0.00 0.03 0.09 0.05 0.02 0.100.05 0.09 SEQID-01757 B4G1P4 — — 1 0.48 0.19 0.05 0.06 0.05 0.07 0.020.05 0.07 0.03 0.04 0.05 0.08 0.09 SEQID-01758 B4F093 — — 0 0.50 0.090.17 0.03 0.02 0.03 0.00 0.00 0.03 0.01 0.01 0.01 0.04 0.31 SEQID-01759O22424 — — 1 0.51 0.22 0.04 0.11 0.05 0.06 0.01 0.03 0.04 0.04 0.04 0.080.08 0.12 SEQID-01760 B8QXG4 — — 1 0.50 0.18 0.08 0.06 0.04 0.07 0.010.05 0.08 0.03 0.02 0.04 0.07 0.10 SEQID-01761 B6TFX9 — — 1 0.45 0.230.08 0.07 0.02 0.05 0.01 0.03 0.05 0.05 0.02 0.04 0.10 0.05 SEQID-01762B6TDF8 — — 1 0.46 0.21 0.08 0.06 0.04 0.06 0.01 0.01 0.05 0.04 0.02 0.060.06 0.08 SEQID-01763 K7VLV6 — — 1 0.49 0.21 0.06 0.06 0.03 0.06 0.010.03 0.12 0.03 0.02 0.04 0.12 0.16 SEQID-01764 B65J49 — — 0 0.41 0.180.05 0.21 0.03 0.00 0.09 0.03 0.06 0.04 0.05 0.00 0.11 0.01 SEQID-01765P69246 — — 0 0.45 0.18 0.09 0.17 0.01 0.03 0.01 0.07 0.06 0.03 0.02 0.050.09 0.12 SEQID-01766 P80639 — — 0 0.49 0.20 0.04 0.04 0.04 0.09 0.020.04 0.09 0.04 0.05 0.06 0.06 0.11 SEQID-01767 C0HHC4 — — 1 0.50 0.210.04 0.07 0.03 0.05 0.00 0.04 0.08 0.05 0.02 0.09 0.05 0.08 SEQID-01768B4FFR7 — — 1 0.49 0.14 0.07 0.14 0.01 0.03 0.01 0.05 0.07 0.04 0.02 0.050.05 0.22 SEQID-01769 B4G031 — — 1 0.44 0.19 0.07 0.06 0.03 0.08 0.010.04 0.08 0.05 0.04 0.03 0.12 0.08 SEQID-01770 B4F9R4 — — 1 0.43 0.170.07 0.15 0.04 0.03 0.01 0.03 0.03 0.07 0.07 0.04 0.04 0.08 SEQID-01771Q08062 — — 1 0.47 0.24 0.07 0.05 0.04 0.05 0.02 0.04 0.08 0.04 0.02 0.050.08 0.07 SEQID-01772 B6T7G7 — — 1 0.50 0.20 0.05 0.04 0.04 0.06 0.010.02 0.10 0.03 0.02 0.03 0.09 0.11 SEQID-01773 P26301 — — 1 0.46 0.220.06 0.04 0.06 0.06 0.01 0.04 0.09 0.05 0.01 0.07 0.08 0.10 SEQID-01774B6TBZ8 — — 1 0.43 0.23 0.06 0.06 0.04 0.05 0.02 0.06 0.03 0.04 0.02 0.070.10 0.07 SEQID-01775 B6U051 — — 1 0.48 0.21 0.05 0.07 0.03 0.06 0.020.05 0.09 0.04 0.02 0.05 0.08 0.08 SEQID-01776 B6SGX0 — — 0 0.56 0.180.05 0.16 0.01 0.02 0.00 0.01 0.06 0.05 0.04 0.03 0.09 0.21 SEQID-01777Q4W1F6 — — 1 0.56 0.21 0.13 0.01 0.01 0.04 0.02 0.03 0.10 0.02 0.05 0.040.05 0.12 SEQID-01778 B6SNY0 — — 1 0.40 0.24 0.10 0.13 0.02 0.04 0.010.06 0.03 0.05 0.04 0.02 0.12 0.02 SEQID-01779 Q41764 — — 1 0.44 0.180.05 0.08 0.04 0.10 0.01 0.05 0.06 0.02 0.01 0.06 0.06 0.10 SEQID-01780B6T4H7 — — 1 0.56 0.18 0.06 0.10 0.03 0.03 0.01 0.02 0.02 0.06 0.08 0.050.06 0.17 SEQID-01781 P25460 — — 1 0.52 0.17 0.05 0.11 0.03 0.01 0.020.03 0.04 0.05 0.04 0.08 0.03 0.16 SEQID-01782 B4FUS2 — — 1 0.51 0.200.02 0.16 0.05 0.07 0.01 0.04 0.04 0.04 0.03 0.04 0.09 0.12 SEQID-01783P06673 — — 0 0.33 0.16 0.10 0.04 0.02 0.01 0.04 0.17 0.02 0.04 0.00 0.010.11 0.01 SEQID-01784 B4F9R6 — — 1 0.50 0.16 0.03 0.12 0.06 0.02 0.010.04 0.05 0.02 0.04 0.05 0.06 0.11 SEQID-01785 B

T7B2 — — 1 0.43 0.20 0.05 0.17 0.05 0.04 0.00 0.03 0.09 0.04 0.04 0.040.11 0.09 SEQID-01786

4FB55 — — 1 0.44 0.20 0.07 0.09 0.05 0.08 0.01 0.04 0.06 0.03 0.01 0.090.07 0.09 SEQID-01787 P45633 — — 1 0.42 0.17 0.07 0.16 0.04 0.05 0.030.03 0.05 0.04 0.03 0.04 0.06 0.11 SEQID-01788 K7UJH1 — — 1 0.45 0.190.07 0.08 0.04 0.05 0.01 0.04 0.05 0.06 0.02 0.06 0.06 0.07 SEQID-01789B6SI09 — — 1 0.45 0.24 0.16 0.11 0.03 0.02 0.02 0.01 0.05 0.07 0.05 0.020.13 0.01 SEQID-01790 B4FAV3 — — 1 0.51 0.21 0.04 0.10 0.03 0.06 0.010.05 0.07 0.03 0.01 0.06 0.07 0.14 SEQID-01791 P00333 — — 1 0.50 0.210.06 0.05 0.05 0.04 0.03 0.02 0.09 0.05 0.04 0.06 0.06 0.08 SEQID-01792P05494 — — 0 0.42 0.25 0.07 0.09 0.04 0.05 0.01 0.06 0.08 0.04 0.01 0.070.11 0.06 SEQID-01793 P19023 — — 0 0.44 0.24 0.07 0.09 0.03 0.06 0.000.05 0.07 0.05 0.02 0.07 0.09 0.05 SEQID-01794 A4GUI1 — — 1 0.45 0.170.04 0.09 0.04 0.07 0.01 0.03 0.06 0.05 0.05 0.04 0.07 0.04 SEQID-01795B4FGQ6 — — 0 0.47 0.19 0.03 0.17 0.02 0.01 0.01 0.06 0.04 0.03 0.02 0.040.07 0.18 SEQID-01796 B

T2K5 — — 0 0.54 0.22 0.05 0.15 0.01 0.02 0.00 0.04 0.06 0.01 0.02 0.050.13 0.21 SEQID-01797 B4FJ41 — — 1 0.49 0.22 0.13 0.05 0.00 0.05 0.000.08 0.01 0.08 0.05 0.04 0.11 0.06 SEQID-01798 Q08275 — — 0 0.44 0.200.08 0.15 0.01 0.09 0.01 0.01 0.09 0.04 0.02 0.03 0.07 0.08 SEQID-01799B

6SK03 — — 1 0.46 0.17 0.02 0.09 0.05 0.06 0.01 0.04 0.08 0.05 0.03 0.050.07 0.06 SEQID-01800 B6TR92 — — 1 0.49 0.20 0.05 0.03 0.05 0.07 0.020.04 0.06 0.04 0.01 0.06 0.08 0.12 SEQID-01801 B6SP06 — — 1 0.22 0.070.02 0.13 0.03 0.10 0.03 0.02 0.04 0.22 0.02 0.02 0.03 0.04 SEQID-01802B6SJ08 — — 0 0.48 0.20 0.05 0.18 0.04 0.04 0.01 0.02 0.04 0.04 0.02 0.040.09 0.11 SEQID-01803 B6UHQ3 — — 1 0.39 0.19 0.17 0.08 0.01 0.06 0.020.07 0.04 0.04 0.05 0.01 0.13 0.02 SEQID-01804 B4F8D6 — — 1 0.38 0.170.07 0.07 0.04 0.08 0.04 0.05 0.04 0.05 0.02 0.02 0.10 0.04 SEQID-01805B4FHH2 — — 1 0.48 0.24 0.05 0.12 0.03 0.04 0.01 0.03 0.09 0.04 0.02 0.060.10 0.08 SEQID-01806 C0PM74 — — 1 0.47 0.22 0.06 0.07 0.02 0.08 0.020.04 0.06 0.03 0.03 0.06 0.10 0.11 SEQID-01807 B4F7Y1 — — 1 0.54 0.220.06 0.10 0.04 0.03 0.01 0.04 0.07 0.03 0.02 0.05 0.10 0.18 SEQID-01808Q84RL7 — — 1 0.49 0.26 0.10 0.05 0.02 0.05 0.01 0.02 0.02 0.07 0.03 0.080.09 0.04 SEQID-01809 C0PCQ6 — — 1 0.49 0.20 0.04 0.13 0.01 0.03 0.020.04 0.08 0.07 0.02 0.05 0.06 0.10 SEQID-01810 B4FBF6 — — 1 0.47 0.200.09 0.06 0.03 0.03 0.02 0.08 0.03 0.05 0.01 0.05 0.08 0.08 SEQID-01811B6THG9 — — 0 0.42 0.16 0.06 0.11 0.04 0.08 0.00 0.03 0.08 0.04 0.03 0.050.08 0.11 SEQID-01812 O24573 — — 0 0.48 0.25 0.06 0.04 0.03 0.07 0.010.02 0.10 0.04 0.01 0.06 0.10 0.11 SEQID-01813 B4FRC6 — — 1 0.45 0.230.10 0.03 0.04 0.05 0.02 0.05 0.01 0.06 0.01 0.02 0.12 0.04 SEQID-01814P04709 — — 1 0.46 0.19 0.06 0.08 0.05 0.05 0.01 0.04 0.03 0.06 0.01 0.060.09 0.08 SEQID-01815 Q41745 — — 1 0.57 0.26 0.06 0.09 0.01 0.04 0.010.03 0.05 0.03 0.02 0.06 0.12 0.07 SEQID-01816 B4FTU3 — — 1 0.53 0.290.08 0.06 0.04 0.01 0.02 0.04 0.03 0.04 0.02 0.06 0.14 0.06 SEQID-01817C0PMH6 — — 1 0.53 0.25 0.07 0.05 0.03 0.02 0.01 0.03 0.04 0.03 0.02 0.070.10 0.06 SEQID-01818

4F987 — — 1 0.43 0.19 0.07 0.10 0.01 0.07 0.01 0.02 0.06 0.07 0.03 0.040.07 0.03 SEQID-01819

4FUE0 — — 1 0.51 0.21 0.05 0.06 0.03 0.07 0.02 0.03 0.10 0.03 0.03 0.080.07 0.12 SEQID-01820

B4FQ44 — — 1 0.44 0.19 0.06 0.09 0.05 0.06 0.02 0.02 0.05 0.05 0.02 0.060.07 0.05 SEQID-01821 B4FAD9 — — 1 0.51 0.27 0.03 0.04 0.07 0.06 0.010.03 0.09 0.03 0.01 0.08 0.11 0.10 SEQID-01822

A1R6 — — 1 0.53 0.29 0.05 0.06 0.04 0.02 0.01 0.04 0.05 0.05 0.02 0.090.13 0.04 SEQID-01823 D3YKV1 — — 1 0.44 0.22 0.07 0.06 0.05 0.07 0.010.03 0.07 0.04 0.02 0.09 0.08 0.07 SEQID-01824 C0PHH5 — — 1 0.48 0.250.08 0.07 0.04 0.05 0.01 0.02 0.07 0.05 0.05 0.08 0.09 0.07 SEQID-01825B6UDM4 — — 1 0.54 0.23 0.06 0.09 0.01 0.04 0.01 0.03 0.03 0.05 0.03 0.030.15 0.09 SEQID-01826

6SPL7 — — 0 0.53 0.21 0.07 0.02 0.01 0.04 0.02 0.04 0.10 0.05 0.00 0.010.04 0.12 SEQID-01827

4FC92 — — 0 0.46 0.17 0.06 0.05 0.03 0.04 0.02 0.09 0.06 0.05 0.04 0.030.08 0.04 SEQID-01828 B4FIA6 — — 0 0.42 0.23 0.13 0.11 0.04 0.03 0.000.02 0.07 0.07 0.02 0.05 0.11 0.10 SEQID-01829 B4FEE7 — — 0 0.33 0.130.08 0.22 0.05 0.04 0.05 0.03 0.03 0.04 0.06 0.04 0.02 0.08 SEQID-01830B6SHT0 — — 1 0.46 0.22 0.09 0.09 0.04 0.07 0.01 0.02 0.07 0.04 0.01 0.040.08 0.08 SEQID-01831 P19950 — — 0 0.44 0.18 0.06 0.17 0.02 0.05 0.010.02 0.07 0.06 0.03 0.05 0.07 0.08 SEQID-01832 B4FD90 — — 1 0.41 0.200.06 0.13 0.03 0.06 0.01 0.06 0.05 0.05 0.03 0.08 0.06 0.08 SEQID-01833B4FH4

— — 1 0.43 0.21 0.11 0.09 0.04 0.07 0.04 0.01 0.06 0.03 0.06 0.03 0.060.05 SEQID-01834 B6SNQ7 — — 0 0.43 0.20 0.06 0.18 0.01 0.04 0.01 0.050.05 0.04 0.00 0.06 0.07 0.11 SEQID-01835 B4G250 — — 1 0.46 0.16 0.040.10 0.04 0.05 0.00 0.03 0.13 0.03 0.02 0.04 0.06 0.09 SEQID-01836B6UD91 — — 1 0.38 0.20 0.16 0.08 0.02 0.09 0.03 0.02 0.07 0.05 0.01 0.040.11 0.05 SEQID-01837 B6UI23 — — 1 0.34 0.17 0.18 0.12 0.01 0.09 0.030.03 0.05 0.03 0.02 0.03 0.08 0.04 SEQID-01838 B6T1F2 — — 1 0.50 0.220.03 0.13 0.03 0.04 0.01 0.03 0.04 0.05 0.05 0.06 0.07 0.11 SEQID-01839P49076 — — 1 0.52 0.24 0.04 0.08 0.06 0.07 0.00 0.04 0.07 0.03 0.02 0.060.12 0.07 SEQID-01840 P12653 — — 1 0.48 0.23 0.08 0.05 0.04 0.04 0.020.03 0.09 0.02 0.02 0.03 0.13 0.08 SEQID-01841 B4F9G6 — — 1 0.52 0.200.06 0.09 0.01 0.06 0.00 0.02 0.05 0.03 0.02 0.05 0.08 0.16 SEQID-01842B4FAM6 — — 1 0.51 0.23 0.05 0.13 0.01 0.02 0.02 0.03 0.09 0.03 0.04 0.060.11 0.15 SEQID-01843

4FE06 — — 1 0.45 0.21 0.06 0.10 0.03 0.08 0.01 0.02 0.08 0.03 0.02 0.050.07 0.07 SEQID-01844

6TB84 — — 1 0.42 0.21 0.06 0.08 0.03 0.08 0.01 0.05 0.09 0.02 0.03 0.060.08 0.08 SEQID-01845 A2SZW8 — — 1 0.47 0.18 0.07 0.07 0.02 0.08 0.010.04 0.06 0.04 0.03 0.04 0.07 0.09 SEQID-01846 P41980 — — 1 0.47 0.210.09 0.04 0.06 0.05 0.00 0.04 0.07 0.05 0.04 0.04 0.11 0.08 SEQID-01847C4J9Y2 — — 1 0.46 0.23 0.08 0.05 0.03 0.05 0.02 0.04 0.07 0.05 0.03 0.020.13 0.06 SEQID-01848 D4F848 — — 0 0.49 0.27 0.07 0.06 0.01 0.06 0.000.02 0.08 0.05 0.01 0.06 0.10 0.10 SEQID-01849

6TKC5 — — 1 0.47 0.21 0.08 0.07 0.02 0.04 0.00 0.03 0.08 0.04 0.04 0.070.09 0.03 SEQID-01850 P29023 — — 1 0.34 0.13 0.08 0.08 0.06 0.03 0.060.07 0.03 0.09 0.02 0.02 0.05 0.04 SEQID-01851 B4F8K1 — — 1 0.47 0.220.04 0.12 0.07 0.01 0.00 0.04 0.11 0.03 0.02 0.07 0.10 0.13 SEQID-01852

4FXR6 — — 1 0.26 0.08 0.05 0.11 0.02 0.06 0.05 0.02 0.05 0.19 0.04 0.020.02 0.03 SEQID-01853 Q41814 — — 0 0.40 0.03 0.03 0.00 0.00 0.01 0.000.00 0.02 0.02 0.02 0.00 0.02 0.15 SEQID-01854 D4F9T3 — — 1 0.41 0.220.09 0.09 0.02 0.06 0.02 0.03 0.09 0.05 0.02 0.07 0.07 0.06 SEQID-01855Q6XZ78 — — 1 0.48 0.22 0.09 0.06 0.05 0.08 0.02 0.01 0.06 0.05 0.02 0.040.11 0.08 SEQID-01856

4FRJ1 — — 0 0.48 0.25 0.07 0.05 0.05 0.05 0.01 0.03 0.07 0.05 0.01 0.050.11 0.09 SEQID-01857 P93629 — — 1 0.51 0.23 0.05 0.03 0.04 0.06 0.040.04 0.06 0.06 0.03 0.06 0.06 0.08 SEQID-01858 B4FRI

— — 1 0.43 0.19 0.11 0.07 0.03 0.06 0.02 0.03 0.05 0.04 0.03 0.04 0.080.07 SEQID-01859 B6TGG7 — — 1 0.44 0.21 0.07 0.08 0.05 0.06 0.02 0.020.05 0.06 0.03 0.08 0.06 0.06 SEQID-01860 P30792 — — 1 0.46 0.23 0.060.06 0.05 0.09 0.01 0.04 0.06 0.05 0.03 0.05 0.09 0.07 SEQID-01861

6TZ53 — — 1 0.51 0.25 0.08 0.07 0.02 0.02 0.01 0.03 0.04 0.06 0.03 0.080.11 0.04 SEQID-01862 B6SH97 — — 1 0.44 0.22 0.08 0.10 0.03 0.06 0.010.03 0.07 0.04 0.04 0.07 0.08 0.06 SEQID-01863 B7ZZ42 — — 1 0.45 0.210.06 0.07 0.05 0.08 0.01 0.04 0.10 0.04 0.01 0.07 0.07 0.09 SEQID-01864K7UD35 — — 1 0.47 0.21 0.06 0.11 0.03 0.06 0.01 0.03 0.05 0.04 0.03 0.040.10 0.05 SEQID-01865 Q9

V61 — — 1 0.45 0.19 0.05 0.07 0.04 0.05 0.01 0.08 0.15 0.02 0.02 0.050.10 0.12 SEQID-01866 F1SS64 — — 1 0.45 0.19 0.05 0.07 0.04 0.05 0.010.08 0.15 0.02 0.02 0.05 0.10 0.12 SEQID-01867 Q9TV62 — — 1 0.45 0.180.05 0.07 0.04 0.05 0.01 0.08 0.15 0.02 0.02 0.05 0.10 0.12 SEQID-01868P79293 — — 1 0.44 0.19 0.05 0.08 0.05 0.05 0.01 0.07 0.15 0.02 0.02 0.040.11 0.12 SEQID-01869 P68137 — — 1 0.47 0.20 0.05 0.07 0.03 0.06 0.010.03 0.09 0.04 0.03 0.08 0.07 0.06 SEQID-01870 I3L8Q0 — — 1 0.45 0.190.06 0.09 0.02 0.03 0.01 0.05 0.12 0.03 0.03 0.06 0.05 0.09 SEQID-01871F1RQQ8 — — 1 0.45 0.21 0.05 0.10 0.06 0.06 0.01 0.04 0.09 0.03 0.03 0.060.09 0.06 SEQID-01872 F1RHL9 — — 1 0.44 0.20 0.05 0.09 0.05 0.06 0.010.07 0.11 0.02 0.03 0.07 0.09 0.07 SEQID-01873 Q5XLD3 — — 1 0.50 0.200.02 0.07 0.05 0.07 0.01 0.04 0.08 0.04 0.05 0.04 0.10 0.10 SEQID-01874F1RUN2 — — 1 0.46 0.19 0.05 0.07 0.02 0.06 0.05 0.04 0.11 0.01 0.04 0.040.11 0.11 SEQID-01875 Q1KYT0 — — 1 0.48 0.23 0.06 0.06 0.05 0.06 0.010.03 0.08 0.05 0.02 0.06 0.09 0.10 SEQID-01876 F1RFH9 — — 1 0.49 0.250.06 0.07 0.04 0.05 0.02 0.03 0.09 0.04 0.02 0.07 0.10 0.06 SEQID-01877F15HL9 — — 1 0.48 0.23 0.07 0.08 0.03 0.06 0.02 0.03 0.08 0.04 0.03 0.070.08 0.03 SEQID-01878 F1RU49 — — 1 0.43 0.20 0.06 0.10 0.04 0.06 0.010.07 0.11 0.03 0.03 0.05 0.10 0.06 SEQID-01879 P00355 — — 1 0.52 0.220.06 0.04 0.05 0.07 0.01 0.02 0.04 0.05 0.04 0.07 0.06 0.09 SEQID-01880P11607 — — 1 0.50 0.25 0.05 0.06 0.04 0.05 0.03 0.03 0.09 0.03 0.01 0.070.09 0.07 SEQID-01881 F1SRI8 — — 1 0.46 0.20 0.04 0.06 0.04 0.07 0.010.03 0.09 0.03 0.02 0.07 0.06 0.11 SEQID-01882 F1SFA7 — — 1 0.25 0.120.07 0.09 0.04 0.04 0.01 0.03 0.06 0.17 0.01 0.03 0.05 0.05 SEQID-01883F

SHW9 — — 1 0.47 0.15 0.05 0.03 0.06 0.08 0.01 0.05 0.06 0.01 0.04 0.050.07 0.16 SEQID-01884 Q9GIV4 — — 1 0.47 0.11 0.04 0.04 0.04 0.05 0.100.04 0.05 0.03 0.06 0.02 0.03 0.14 SEQID-01885 A1XQT6 — — 0 0.44 0.180.08 0.03 0.05 0.05 0.01 0.04 0.14 0.03 0.01 0.05 0.08 0.12 SEQID-01886D0G7F6 — — 1 0.49 0.23 0.08 0.05 0.05 0.05 0.02 0.04 0.09 0.05 0.03 0.060.07 0.10 SEQID-01887 P16960 — — 1 0.44 0.21 0.05 0.08 0.03 0.05 0.020.04 0.11 0.04 0.03 0.04 0.11 0.05 SEQID-01888 F1RZQ6 — — 1 0.50 0.210.07 0.08 0.03 0.05 0.01 0.05 0.02 0.05 0.01 0.06 0.09 0.09 SEQID-01889Q5XLD2 — — 1 0.49 0.16 0.06 0.05 0.05 0.09 0.01 0.05 0.10 0.04 0.01 0.060.05 0.11 SEQID-01890 Q7SIB7 — — 1 0.52 0.23 0.06 0.04 0.05 0.06 0.020.02 0.08 0.05 0.02 0.05 0.09 0.12 SEQID-01891 F1RVL5 — — 1 0.46 0.200.04 0.05 0.04 0.07 0.02 0.03 0.10 0.03 0.03 0.05 0.07 0.09 SEQID-01892P00339 — — 1 0.54 0.28 0.04 0.05 0.05 0.05 0.01 0.03 0.07 0.04 0.04 0.070.11 0.09 SEQID-01893 F1RH20 — — 1 0.46 0.20 0.04 0.07 0.03 0.06 0.010.04 0.11 0.04 0.02 0.05 0.07 0.10 SEQID-01894 Q55154 — — 1 0.49 0.180.04 0.06 0.04 0.07 0.02 0.02 0.06 0.03 0.06 0.04 0.09 0.09 SEQID-01895B5KJG2 — — 1 0.47 0.18 0.06 0.10 0.03 0.05 0.01 0.03 0.10 0.04 0.04 0.060.08 0.09 SEQID-01896 F1SHX0 — — 1 0.47 0.17 0.04 0.07 0.04 0.07 0.010.05 0.07 0.02 0.05 0.05 0.07 0.13 SEQID-01897 P02540 — — 1 0.37 0.190.06 0.13 0.04 0.05 0.00 0.08 0.14 0.02 0.02 0.04 0.10 0.05 SEQID-01898F15E14 — — 1 0.48 0.22 0.06 0.07 0.04 0.06 0.01 0.04 0.06 0.05 0.02 0.090.08 0.08 SEQID-01899 Q2HYU2 — — 1 0.48 0.22 0.05 0.09 0.04 0.05 0.020.04 0.07 0.05 0.03 0.06 0.08 0.06 SEQID-01900 F1SM75 — — 1 0.44 0.180.05 0.07 0.04 0.05 0.01 0.04 0.10 0.03 0.03 0.05 0.07 0.09 SEQID-01901Q4PS85 — — 1 0.43 0.16 0.03 0.05 0.04 0.04 0.00 0.06 0.07 0.09 0.03 0.030.09 0.08 SEQID-01902 Q75NG9 — — 1 0.38 0.14 0.05 0.12 0.02 0.06 0.000.06 0.21 0.01 0.03 0.04 0.07 0.16 SEQID-01903 F1SQT3 — — 1 0.46 0.210.07 0.07 0.02 0.03 0.02 0.04 0.06 0.04 0.01 0.04 0.10 0.07 SEQID-01904P33198 — — 1 0.50 0.19 0.05 0.07 0.04 0.07 0.02 0.05 0.05 0.04 0.04 0.070.07 0.09 SEQID-01905 F1SMN5 — — 1 0.44 0.20 0.05 0.06 0.03 0.06 0.020.03 0.08 0.06 0.03 0.05 0.05 0.07 SEQID-01906 Q2HYU1 — — 1 0.44 0.210.04 0.12 0.04 0.07 0.02 0.04 0.07 0.04 0.03 0.05 0.10 0.06 SEQID-01907P08059 — — 1 0.52 0.20 0.04 0.06 0.05 0.05 0.00 0.05 0.07 0.04 0.05 0.060.10 0.08 SEQID-01908 F1SG00 — — 0 0.38 0.17 0.07 0.08 0.02 0.07 0.000.07 0.25 0.01 0.01 0.03 0.11 0.13 SEQID-01909 F1RPS8 — — 0 0.45 0.250.07 0.09 0.03 0.06 0.00 0.05 0.07 0.05 0.01 0.08 0.10 0.07 SEQID-01910P16276 — — 1 0.47 0.22 0.05 0.07 0.05 0.06 0.02 0.04 0.06 0.05 0.04 0.060.09 0.08 SEQID-01911 13L953 — — 1 0.44 0.22 0.06 0.10 0.01 0.05 0.020.06 0.10 0.04 0.03 0.03 0.09 0.05 SEQID-01912 P01965 — — 0 0.55 0.220.09 0.03 0.04 0.03 0.01 0.03 0.02 0.04 0.10 0.00 0.14 0.09 SEQID-01913P02067 — — 1 0.54 0.26 0.06 0.05 0.06 0.06 0.01 0.04 0.06 0.05 0.07 0.010.13 0.09 SEQID-01914 Q7M2W6 — — 1 0.48 0.18 0.03 0.12 0.01 0.06 0.000.02 0.09 0.02 0.06 0.06 0.08 0.06 SEQID-01915 F1RT61 — — 0 0.18 0.060.09 0.09 0.03 0.03 0.00 0.04 0.06 0.21 0.01 0.01 0.03 0.05 SEQID-01916I3LB76 — — 1 0.46 0.19 0.05 0.14 0.02 0.05 0.01 0.03 0.13 0.02 0.03 0.020.12 0.14 SEQID-01917 F1RM62 — — 1 0.38 0.22 0.10 0.10 0.00 0.03 0.010.04 0.10 0.03 0.06 0.03 0.11 0.02 SEQID-01918 F6PSL2 — — 0 0.49 0.160.05 0.05 0.06 0.08 0.00 0.04 0.12 0.03 0.01 0.06 0.05 0.11 SEQID-01919P00346 — — 0 0.49 0.25 0.07 0.05 0.04 0.04 0.02 0.03 0.06 0.05 0.02 0.070.10 0.09 SEQID-01920 P11708 — — 1 0.51 0.25 0.06 0.04 0.04 0.08 0.010.03 0.06 0.03 0.02 0.07 0.10 0.11 SEQID-01921 F1RJ25 — — 1 0.41 0.220.08 0.08 0.04 0.05 0.02 0.05 0.08 0.05 0.02 0.06 0.09 0.07 SEQID-01922F1SLA0 — — 0 0.45 0.25 0.08 0.07 0.02 0.06 0.00 0.06 0.08 0.05 0.02 0.070.10 0.05 SEQID-01923 F1RK48 — — 1 0.35 0.16 0.06 0.07 0.03 0.06 0.010.05 0.15 0.06 0.03 0.04 0.09 0.05 SEQID-01924 F1SU23 — — 1 0.39 0.160.05 0.11 0.03 0.09 0.01 0.06 0.05 0.03 0.03 0.01 0.11 0.06 SEQID-01925I3LJX2 — — 0 0.23 0.09 0.10 0.07 0.02 0.05 0.01 0.03 0.07 0.17 0.00 0.010.04 0.06 SEQID-01926 F1SHA2 — — 0 0.49 0.24 0.05 0.04 0.04 0.04 0.040.06 0.10 0.05 0.03 0.07 0.10 0.07 SEQID-01927 F1STM4 — — 1 0.52 0.210.06 0.06 0.04 0.05 0.01 0.03 0.07 0.04 0.03 0.07 0.06 0.11 SEQID-01928F1RIS3 — — 1 0.41 0.22 0.07 0.11 0.00 0.04 0.03 0.03 0.10 0.04 0.04 0.020.14 0.05 SEQID-01929 I3LP30 — — 1 0.49 0.22 0.03 0.06 0.05 0.04 0.010.07 0.15 0.01 0.02 0.05 0.13 0.13 SEQID-01930 F1S557 — — 1 0.45 0.210.04 0.08 0.05 0.05 0.02 0.05 0.08 0.03 0.04 0.06 0.10 0.06 SEQID-01931B5DGM7 — — 1 0.47 0.19 0.07 0.06 0.04 0.05 0.02 0.05 0.07 0.04 0.04 0.050.09 0.08 SEQID-01932 B5DGR2 — — 1 0.53 0.22 0.07 0.05 0.05 0.07 0.010.01 0.05 0.05 0.05 0.07 0.05 0.09 SEQID-01933 B5DGM8 — — 1 0.47 0.190.07 0.06 0.04 0.05 0.02 0.05 0.06 0.04 0.04 0.05 0.09 0.08 SEQID-01934B5DGQ6 — — 1 0.48 0.22 0.07 0.05 0.05 0.08 0.02 0.03 0.07 0.05 0.03 0.070.08 0.11 SEQID-01935 B5DGQ7 — — 1 0.48 0.21 0.07 0.05 0.05 0.08 0.020.03 0.07 0.05 0.03 0.07 0.08 0.11 SEQID-01936 B5DG40 — — 1 0.46 0.200.05 0.07 0.03 0.06 0.01 0.03 0.08 0.04 0.03 0.0

0.07 0.06 SEQID-01937 B5DGP0 — — 1 0.50 0.20 0.02 0.07 0.05 0.08 0.010.02 0.08 0.05 0.05 0.04 0.09 0.10 SEQID-01938 B5DGL3 — — 1 0.51 0.230.07 0.04 0.05 0.06 0.02 0.03 0.08 0.06 0.03 0.07 0.07 0.11 SEQID-01939B5DGG5 — — 1 0.50 0.19 0.03 0.07 0.04 0.08 0.01 0.03 0.08 0.05 0.05 0.040.09 0.10 SEQID-01940 Q91472 — — 0 0.41 0.18 0.07 0.06 0.02 0.09 0.000.04 0.22 0.01 0.00 0.04 0.11 0.15 SEQID-01941 B5DGU1 — — 1 0.49 0.210.06 0.09 0.03 0.06 0.02 0.03 0.08 0.04 0.04 0.08 0.07 0.09 SEQID-01942B5DH12 — — 0 0.43 0.18 0.08 0.04 0.05 0.09 0.00 0.04 0.11 0.04 0.01 0.040.07 0.10 SEQID-01943 B5DG55 — — 1 0.48 0.21 0.05 0.08 0.05 0.06 0.010.04 0.09 0.03 0.04 0.06 0.09 0.09 SEQID-01944 B5DFX

— — 1 0.53 0.22 0.07 0.03 0.05 0.07 0.02 0.02 0.06 0.05 0.03 0.05 0.090.12 SEQID-01945 B5DGT1 — — 0 0.43 0.18 0.08 0.04 0.05 0.09 0.00 0.040.12 0.04 0.01 0.04 0.07 0.10 SEQID-01946 Q7ZZN0 — — 1 0.46 0.18 0.060.04 0.04 0.07 0.01 0.05 0.13 0.03 0.01 0.06 0.07 0.10 SEQID-01947B5DGT9 — — 1 0.52 0.19 0.06 0.07 0.04 0.05 0.01 0.02 0.09 0.04 0.05 0.060.08 0.12 SEQID-01948 O13093 — — 1 0.54 0.18 0.05 0.06 0.03 0.06 0.000.04 0.14 0.02 0.03 0.04 0.09 0.20 SEQID-01949 B5DGM5 — — 0 0.49 0.230.05 0.07 0.01 0.09 0.01 0.02 0.09 0.05 0.01 0.07 0.09 0.14 SEQID-01950B5DG45 — — 1 0.43 0.18 0.07 0.07 0.04 0.06 0.02 0.02 0.10 0.03 0.00 0.060.05 0.11 SEQID-01951 BS0H15 — — 0 0.55 0.17 0.10 0.01 0.02 0.11 0.030.03 0.09 0.03 0.02 0.06 0.08 0.14 SEQID-01952 B5X1G7 — — 1 0.49 0.260.07 0.06 0.04 0.07 0.01 0.03 0.09 0.05 0.01 0.07 0.09 0.10 SEQID-01953B5DGZ4 — — 1 0.39 0.14 0.05 0.11 0.02 0.05 0.00 0.04 0.25 0.01 0.03 0.040.06 0.17 SEQID-01954 Q98SJ9 — — 1 0.57 0.26 0.05 0.03 0.06 0.04 0.030.02 0.09 0.05 0.03 0.09 0.09 0.10 SEQID-01955 B5DG10 — — 1 0.52 0.220.06 0.05 0.04 0.05 0.01 0.03 0.07 0.05 0.03 0.08 0.06 0.12 SEQID-01956B5RI24 — — 1 0.43 0.20 0.05 0.07 0.05 0.08 0.01 0.08 0.10 0.02 0.03 0.080.08 0.04 SEQID-01957 B5DGZ1 — — 1 0.51 0.20 0.07 0.07 0.03 0.05 0.010.05 0.03 0.05 0.01 0.09 0.06 0.10 SEQID-01958 B5DG5S2 — — 1 0.49 0.200.04 0.05 0.04 0.07 0.02 0.05 0.06 0.04 0.03 0.06 0.09 0.10 SEQID-01959B5DFT9 — — 1 0.46 0.19 0.03 0.11 0.05 0.08 0.02 0.04 0.06 0.04 0.03 0.040.10 0.06 SEQID-01960 B5DG78 — — 0 0.45 0.24 0.07 0.09 0.03 0.06 0.010.05 0.06 0.05 0.03 0.07 0.10 0.07 SEQID-01961 B5DG72 — — 1 0.50 0.210.05 0.05 0.04 0.07 0.01 0.03 0.05 0.06 0.03 0.08 0.07 0.09 SEQID-01962406714392 — — 1 0.41 0.20 0.05 0.09 0.05 0.04 0.00 0.06 0.08 0.04 0.010.06 0.08 0.06 SEQID-01963 409935420 — — 1 0.42 0.20 0.05 0.09 0.05 0.040.00 0.06 0.08 0.04 0.01 0.06 0.08 0.06 SEQID-01964 291565678 — — 1 0.450.23 0.09 0.08 0.05 0.06 0.00 0.03 0.12 0.05 0.01 0.07 0.09 0.08SEQID-01965 291568131 — — 1 0.40 0.21 0.07 0.09 0.04 0.07 0.00 0.05 0.100.03 0.02 0.06 0.08 0.08 SEQID-01966 406715237 — — 1 0.42 0.22 0.07 0.090.03 0.08 0.00 0.04 0.10 0.04 0.02 0.06 0.09 0.08 SEQID-01967 406714893— — 1 0.45 0.22 0.05 0.08 0.04 0.07 0.02 0.03 0.10 0.04 0.01 0.06 0.080.07 SEQID-01968 291571801 — — 1 0.45 0.22 0.05 0.08 0.04 0.07 0.02 0.030.10 0.04 0.01 0.06 0.08 0.07 SEQID-01969 406715272 — — 1 0.44 0.23 0.070.08 0.05 0.05 0.02 0.04 0.11 0.05 0.03 0.09 0.07 0.05 SEQID-01970406712836 — — 0 0.43 0.21 0.08 0.07 0.04 0.06 0.01 0.05 0.08 0.04 0.050.07 0.07 0.05 SEQID-01971 406716509 — — 1 0.38 0.14 0.07 0.10 0.02 0.040.00 0.17 0.10 0.01 0.02 0.02 0.07 0.07 SEQID-01972 406712937 — — 1 0.390.20 0.07 0.06 0.05 0.06 0.01 0.08 0.09 0.03 0.02 0.05 0.10 0.06SEQID-01973 304281792 — — 1 0.38 0.19 0.06 0.10 0.04 0.05 0.01 0.06 0.060.05 0.03 0.08 0.06 0.05 SEQID-01974 406711415 — — 1 0.48 0.25 0.06 0.060.03 0.07 0.01 0.02 0.05 0.04 0.03 0.07 0.09 0.06 SEQID-01975 291566625— — 1 0.49 0.25 0.06 0.06 0.08 0.07 0.01 0.02 0.05 0.04 0.03 0.06 0.090.06 SEQID-01976 406712246 — — 1 0.40 0.17 0.04 0.11 0.06 0.04 0.00 0.030.07 0.03 0.01 0.05 0.07 0.04 SEQID-01977 406715559 — — 1 0.57 0.23 0.060.04 0.04 0.04 0.01 0.04 0.03 0.05 0.07 0.07 0.10 0.04 SEQID-019784067161

2 — — 1 0.44 0.25 0.05 0.12 0.03 0.06 0.00 0.04 0.13 0.04 0.02 0.08 0.100.07 SEQID-01979 406711547 — — 1 0.40 0.20 0.06 0.08 0.10 0.04 0.01 0.050.05 0.06 0.01 0.07 0.06 0.02 SEQID-01980 406715412 — — 1 0.42 0.22 0.040.11 0.04 0.07 0.00 0.05 0.09 0.04 0.02 0.06 0.09 0.05 SEQID-01981406712949 — — 1 0.49 0.22 0.06 0.08 0.03 0.08 0.00 0.03 0.09 0.05 0.030.08 0.06 0.07 SEQID-01982 291570166 — — 1 0.44 0.17 0.04 0.07 0.04 0.050.01 0.07 0.09 0.05 0.03 0.07 0.07 0.07 SEQID-01983 291569320 — — 1 0.490.22 0.06 0.08 0.03 0.07 0.00 0.03 0.09 0.05 0.03 0.08 0.06 0.07SEQID-01984 406715542 — — 1 0.47 0.21 0.07 0.06 0.04 0.06 0.01 0.03 0.070.05 0.04 0.05 0.09 0.06 SEQID-01985 406714412 — — 0 0.42 0.15 0.05 0.090.04 0.06 0.01 0.04 0.10 0.05 0.04 0.04 0.08 0.11 SEQID-01986 406711071— — 0 0.47 0.27 0.08 0.07 0.04 0.06 0.00 0.05 0.11 0.06 0.00 0.09 0.090.08 SEQID-01987 406712053 — — 1 0.45 0.19 0.05 0.06 0.06 0.06 0.01 0.050.08 0.04 0.03 0.05 0.09 0.06 SEQID-01988 P13550 — — 1 0.45 0.24 0.050.08 0.02 0.06 0.01 0.04 0.11 0.04 0.02 0.08 0.07 0.06 SEQID-01989406715415 — — 1 0.44 0.25 0.04 0.08 0.04 0.08 0.01 0.05 0.10 0.04 0.020.07 0.09 0.05 SEQID-01990 291570822 — — 1 0.49 0.19 0.02 0.07 0.03 0.090.02 0.04 0.07 0.05 0.01 0.04 0.05 0.07 SEQID-01991 157042617 — — 1 0.360.18 0.05 0.14 0.05 0.02 0.00 0.07 0.10 0.04 0.01 0.03 0.08 0.02SEQID-01992 406711121 — — 0 0.46 0.22 0.05 0.07 0.06 0.05 0.01 0.08 0.070.03 0.00 0.07 0.10 0.05 SEQID-01993 406715081 — — 1 0.50 0.19 0.06 0.070.02 0.05 0.00 0.05 0.05 0.06 0.03 0.05 0.07 0.03 SEQID-01994 406713986— — 0 0.42 0.25 0.07 0.07 0.03 0.06 0.00 0.08 0.08 0.05 0.00 0.08 0.100.06 SEQID-01995 291570872 — — 0 0.48 0.27 0.07 0.07 0.04 0.05 0.00 0.040.11 0.06 0.00 0.09 0.09 0.08 SEQID-01996 406715991 — — 1 0.46 0.21 0.050.06 0.05 0.07 0.01 0.04 0.06 0.06 0.03 0.06 0.09 0.06 SEQID-01997409938508 — — 1 0.45 0.19 0.05 0.06 0.06 0.07 0.00 0.05 0.08 0.04 0.020.05 0.09 0.07 SEQID-01998 291571972 — — 1 0.51 0.20 0.06 0.07 0.02 0.050.00 0.04 0.06 0.06 0.03 0.05 0.09 0.03 SEQID-01999 291565665 — — 0 0.410.15 0.05 0.09 0.03 0.06 0.01 0.05 0.10 0.05 0.03 0.04 0.08 0.11SEQID-02000 291568537 — — 1 0.49 0.16 0.04 0.05 0.05 0.03 0.01 0.03 0.120.05 0.01 0.05 0.07 0.13 SEQID-02001 1524355 — — 0 0.40 0.23 0.07 0.110.02 0.05 0.01 0.01 0.11 0.05 0.00 0.08 0.07 0.04 SEQID-02002 157042618— — 1 0.35 0.19 0.04 0.13 0.03 0.05 0.01 0.07 0.08 0.04 0.01 0.05 0.080.03 SEQID-02003 291568724 — — 0 0.45 0.25 0.05 0.07 0.03 0.06 0.00 0.050.09 0.05 0.01 0.07 0.09 0.06 SEQID-02004 406716541 — — 0 0.44 0.22 0.060.07 0.04 0.09 0.01 0.05 0.09 0.05 0.01 0.06 0.08 0.09 SEQID-02005291568008 — — 1 0.45 0.21 0.06 0.06 0.04 0.07 0.01 0.04 0.06 0.06 0.030.06 0.09 0.05 SEQID-02006 291567743 — — 1 0.56 0.21 0.06 0.04 0.04 0.040.00 0.04 0.03 0.05 0.07 0.06 0.10 0.03 SEQID-02007 2915693

9 — — 0 0.38 0.17 0.02 0.04 0.04 0.05 0.00 0.22 0.12 0.01 0.02 0.04 0.110.10 SEQID-02008 2114199 — — 0 0.41 0.23 0.09 0.07 0.04 0.07 0.01 0.040.04 0.04 0.00 0.08 0.09 0.06 SEQID-02009 406716545 — — 1 0.52 0.24 0.060.05 0.05 0.03 0.00 0.03 0.05 0.07 0.04 0.07 0.11 0.03 SEQID-02010406710610 — — 1 0.46 0.20 0.04 0.07 0.06 0.07 0.01 0.05 0.07 0.03 0.040.06 0.10 0.06 SEQID-02011 406712941 — — 1 0.43 0.22 0.05 0.07 0.04 0.060.02 0.05 0.08 0.06 0.03 0.06 0.10 0.05 SEQID-02012 406712920 — — 0 0.420.19 0.03 0.04 0.05 0.05 0.00 0.16 0.09 0.01 0.02 0.05 0.12 0.09SEQID-02013 406716507 — — 1 0.44 0.25 0.04 0.10 0.05 0.06 0.01 0.06 0.080.02 0.02 0.07 0.12 0.04 SEQID-02014 406714835 — — 1 0.38 0.17 0.06 0.030.02 0.02 0.01 0.24 0.18 0.01 0.03 0.02 0.12 0.07 SEQID-02015 291566055— — 1 0.49 0.16 0.03 0.05 0.05 0.07 0.01 0.03 0.08 0.04 0.06 0.04 0.060.05 SEQID-02016 409939478 — — 0 0.39 0.05 0.08 0.00 0.00 0.07 0.00 0.010.15 0.00 0.01 0.01 0.00 0.23 SEQID-02017 P72508 — — 0 0.38 0.22 0.110.09 0.04 0.06 0.02 0.04 0.06 0.03 0.00 0.06 0.09 0.03 SEQID-02018291568270 — — 1 0.42 0.22 0.03 0.10 0.03 0.06 0.02 0.05 0.13 0.02 0.010.08 0.05 0.07 SEQID-02019 406714163 — — 1 0.49 0.23 0.06 0.05 0.06 0.020.01 0.03 0.06 0.05 0.03 0.07 0.09 0.00 SEQID-02020 406713173 — — 1 0.440.24 0.07 0.11 0.03 0.07 0.00 0.05 0.08 0.05 0.01 0.07 0.10 0.04SEQID-02021 406711712 — — 1 0.45 0.21 0.07 0.09 0.04 0.07 0.01 0.04 0.120.04 0.01 0.07 0.07 0.12 SEQID-02022 291566390 — — 1 0.43 0.25 0.07 0.100.04 0.06 0.01 0.07 0.08 0.02 0.00 0.05 0.13 0.07 SEQID-02023 291565971— — 1 0.49 0.23 0.07 0.07 0.04 0.07 0.01 0.04 0.08 0.04 0.03 0.08 0.080.07 SEQID-02024 291570193 — — 1 0.46 0.19 0.04 0.07 0.06 0.06 0.01 0.040.08 0.04 0.05 0.06 0.09 0.05 SEQID-02025 406711224 — — 1 0.45 0.21 0.050.05 0.05 0.06 0.01 0.06 0.08 0.03 0.03 0.06 0.09 0.08 SEQID-02026409938720 — — 1 0.45 0.22 0.06 0.09 0.04 0.08 0.01 0.05 0.12 0.04 0.010.08 0.06 0.12 SEQID-02027 406715510 — — 1 0.42 0.19 0.05 0.16 0.05 0.030.01 0.02 0.05 0.06 0.04 0.07 0.05 0.09 SEQID-02028 406716632 — — 0 0.420.15 0.05 0.03 0.02 0.03 0.00 0.02 0.16 0.01 0.00 0.03 0.05 0.15SEQID-02029 291567489 — — 1 0.48 0.22 0.06 0.06 0.04 0.08 0.01 0.03 0.050.05 0.03 0.07 0.07 0.07 SEQID-02030 406715202 — — 1 0.42 0.21 0.04 0.100.04 0.07 0.01 0.05 0.05 0.04 0.03 0.08 0.09 0.04 SEQID-02031 291572127— — 1 0.40 0.21 0.04 0.11 0.04 0.04 0.01 0.03 0.11 0.05 0.01 0.07 0.070.02 SEQID-02032 406710632 — — 1 0.45 0.27 0.08 0.07 0.03 0.05 0.00 0.100.08 0.03 0.00 0.08 0.10 0.08 SEQID-02033 291569653 — — 1 0.45 0.22 0.060.08 0.03 0.06 0.01 0.08 0.07 0.04 0.01 0.04 0.10 0.06 SEQID-02034291568318 — — 1 0.44 0.25 0.04 0.12 0.05 0.05 0.01 0.04 0.09 0.03 0.020.07 0.11 0.06 SEQID-02035 10303060 — — 0 0.39 0.16 0.10 0.09 0.02 0.050.02 0.08 0.04 0.04 0.00 0.05 0.07 0.09 SEQID-02036 406714441 — — 0 0.420.09 0.12 0.06 0.03 0.05 0.00 0.02 0.08 0.03 0.00 0.01 0.04 0.16SEQID-02037 406713502 — — 0 0.49 0.24 0.07 0.06 0.03 0.06 0.01 0.06 0.080.03 0.00 0.08 0.08 0.11 SEQID-02038 406715512 — — 1 0.43 0.22 0.07 0.150.03 0.04 0.01 0.05 0.08 0.04 0.01 0.04 0.08 0.08 SEQID-02039 406716252— — 0 0.36 0.19 0.08 0.08 0.07 0.04 0.00 0.13 0.13 0.02 0.00 0.04 0.110.08 SEQID-02040 291571590 — — 0 0.43 0.21 0.06 0.06 0.04 0.07 0.01 0.040.08 0.04 0.00 0.05 0.11 0.07 SEQID-02041 291571517 — — 1 0.39 0.20 0.060.10 0.03 0.14 0.01 0.04 0.07 0.04 0.02 0.07 0.08 0.06 SEQID-02042155676168 — — 1 0.50 0.24 0.06 0.07 0.03 0.07 0.01 0.05 0.09 0.05 0.030.08 0.09 0.07 SEQID-02043 291565929 — — 0 0.49 0.21 0.11 0.01 0.00 0.050.00 0.04 0.18 0.04 0.00 0.06 0.10 0.14 SEQID-02044 291565691 — — 0 0.420.08 0.14 0.06 0.04 0.03 0.00 0.01 0.10 0.03 0.00 0.01 0.04 0.17SEQID-02045 406713937 — — 0 0.49 0.30 0.05 0.09 0.05 0.05 0.00 0.06 0.080.04 0.01 0.07 0.15 0.06 SEQID-02046 291572098 — — 1 0.41 0.21 0.05 0.090.03 0.06 0.00 0.04 0.17 0.03 0.02 0.07 0.07 0.04 SEQID-02047 291571140— — 1 0.47 0.25 0.04 0.05 0.04 0.08 0.01 0.05 0.06 0.05 0.02 0.06 0.100.07 SEQID-02048 406713289 — — 1 0.42 0.21 0.05 0.05 0.03 0.05 0.00 0.080.19 0.02 0.01 0.06 0.09 0.08 SEQID-02049 406714641 — — 1 0.40 0.20 0.040.11 0.04 0.05 0.01 0.04 0.10 0.04 0.01 0.07 0.07 0.02 SEQID-02050406712535 — — 1 0.40 0.24 0.05 0.04 0.05 0.11 0.00 0.07 0.14 0.02 0.010.07 0.09 0.01 SEQID-02051 291567799 — — 0 0.43 0.21 0.06 0.18 0.01 0.070.01 0.06 0.05 0.03 0.05 0.05 0.08 0.07 SEQID-02052 291569929 — — 0 0.450.24 0.05 0.09 0.03 0.08 0.01 0.04 0.09 0.04 0.00 0.08 0.11 0.08SEQID-02053 406716396 — — 0 0.37 0.13 0.06 0.08 0.06 0.06 0.01 0.07 0.090.05 0.00 0.03 0.05 0.12 SEQID-02054 226536926 — — 1 0.52 0.17 0.08 0.000.08 0.05 0.01 0.04 0.06 0.04 0.04 0.04 0.10 0.08 SEQID-02055 291566672— — 1 0.45 0.20 0.05 0.10 0.03 0.04 0.01 0.04 0.09 0.04 0.03 0.04 0.100.07 SEQID-02056 291567524 — — 1 0.54 0.22 0.06 0.05 0.04 0.03 0.02 0.040.06 0.05 0.03 0.05 0.11 0.01 SEQID-02057 291571685 — — 1 0.46 0.22 0.040.10 0.05 0.07 0.01 0.02 0.08 0.04 0.03 0.08 0.07 0.04 SEQID-02058406711744 — — 1 0.46 0.23 0.06 0.04 0.06 0.05 0.00 0.06 0.07 0.05 0.030.06 0.08 0.05 SEQID-02059 291567802 — — 0 0.52 0.32 0.06 0.08 0.03 0.010.00 0.06 0.04 0.05 0.00 0.12 0.12 0.03 SEQID-02060 406712317 — — 1 0.440.20 0.04 0.04 0.02 0.04 0.00 0.20 0.11 0.01 0.03 0.03 0.12 0.09SEQID-02061 406715474 — — 1 0.44 0.26 0.06 0.09 0.04 0.06 0.01 0.05 0.090.04 0.01 0.07 0.13 0.06 SEQID-02062 291569833 — — 1 0.43 0.24 0.07 0.110.04 0.07 0.00 0.06 0.09 0.04 0.01 0.06 0.10 0.05 SEQID-02063 406715203— — 1 0.43 0.22 0.04 0.11 0.05 0.07 0.01 0.05 0.06 0.04 0.02 0.08 0.100.03 SEQID-02064 406715533 — — 1 0.45 0.23 0.05 0.06 0.04 0.05 0.01 0.060.10 0.04 0.02 0.05 0.11 0.05 SEQID-02065 291570764 — — 1 0.48 0.23 0.070.06 0.05 0.06 0.01 0.03 0.08 0.04 0.03 0.08 0.09 0.06 SEQID-02066291570294 — — 1 0.45 0.20 0.06 0.06 0.05 0.06 0.02 0.04 0.07 0.04 0.020.05 0.08 0.07 SEQID-02067 291565677 — — 0 0.46 0.26 0.07 0.06 0.02 0.070.01 0.01 0.11 0.06 0.00 0.05 0.09 0.12 SEQID-02068 406713927 — — 0 0.440.09 0.05 0.10 0.01 0.07 0.00 0.02 0.08 0.03 0.00 0.02 0.06 0.15SEQID-02069 291565882 — — 1 0.44 0.24 0.12 0.10 0.02 0.05 0.00 0.02 0.080.06 0.01 0.07 0.07 0.04 SEQID-02070 291570798 — — 0 0.44 0.23 0.06 0.130.02 0.03 0.00 0.07 0.13 0.03 0.02 0.07 0.08 0.08 SEQID-02071 406711359— — 1 0.46 0.22 0.08 0.07 0.02 0.05 0.01 0.06 0.07 0.04 0.02 0.06 0.130.06 SEQID-02072 291566660 — — 1 0.46 0.22 0.08 0.07 0.02 0.05 0.01 0.050.07 0.05 0.02 0.06 0.13 0.06 SEQID-02073 406715124 — — 0 0.41 0.24 0.040.14 0.06 0.05 0.02 0.03 0.05 0.03 0.00 0.09 0.08 0.03 SEQID-02074406711662 — — 1 0.48 0.28 0.06 0.06 0.03 0.06 0.02 0.03 0.05 0.06 0.020.09 0.12 0.03 SEQID-02075 406715358 — — 1 0.42 0.19 0.03 0.09 0.03 0.060.04 0.04 0.10 0.02 0.03 0.05 0.08 0.09 SEQID-02076 291568477 — — 1 0.460.21 0.03 0.05 0.06 0.10 0.01 0.04 0.05 0.02 0.02 0.06 0.09 0.08SEQID-02077 291567784 — — 0 0.49 0.21 0.03 0.09 0.06 0.03 0.00 0.05 0.060.07 0.03 0.05 0.09 0.11 SEQID-02078 406711814 — — 1 0.49 0.27 0.06 0.070.04 0.07 0.01 0.04 0.06 0.04 0.03 0.09 0.09 0.05 SEQID-02079 406714225— — 1 0.38 0.18 0.0

0.03 0.09 0.06 0.02 0.06 0.03 0.05 0.01 0.04 0.11 0.04 SEQID-02080291566562 — — 1 0.49 0.19 0.04 0.09 0.05 0.05 0.01 0.02 0.10 0.02 0.040.05 0.10 0.07 SEQID-02081 291566243 — — 1 0.44 0.19 0.05 0.10 0.03 0.050.01 0.04 0.09 0.03 0.06 0.05 0.08 0.05 SEQID-02082 291568601 — — 1 0.490.22 0.07 0.04 0.03 0.04 0.01 0.03 0.08 0.07 0.03 0.06 0.09 0.06SEQID-02083 291568927 — — 1 0.44 0.21 0.06 0.07 0.05 0.05 0.01 0.05 0.080.05 0.02 0.06 0.09 0.06 SEQID-02084 291570378 — — 1 0.46 0.17 0.04 0.080.03 0.05 0.01 0.05 0.07 0.04 0.03 0.06 0.06 0.04 SEQID-02085 406712979— — 1 0.39 0.20 0.08 0.04 0.04 0.04 0.01 0.10 0.10 0.03 0.04 0.05 0.120.05 SEQID-02086 291571158 — — 1 0.47 0.20 0.07 0.06 0.04 0.05 0.01 0.050.07 0.05 0.03 0.06 0.09 0.04 SEQID-02087 291570621 — — 1 0.44 0.22 0.050.09 0.03 0.06 0.00 0.06 0.11 0.03 0.02 0.05 0.09 0.06 SEQID-02088291566536 — — 1 0.42 0.24 0.05 0.04 0.05 0.09 0.00 0.08 0.14 0.02 0.010.07 0.09 0.01 SEQID-02089 291568759 — — 0 0.49 0.38 0.0

0.06 0.01 0.05 0.00 0.02 0.10 0.02 0.00 0.09 0.10 0.05 SEQID-02090291566375 — — 1 0.49 0.20 0.05 0.08 0.01 0.04 0.00 0.08 0.07 0.04 0.010.11 0.06 0.03 SEQID-02091 406715888 — — 0 0.36 0.19 0.04 0.18 0.03 0.030.00 0.06 0.10 0.03 0.00 0.06 0.08 0.07 SEQID-02092 291567786 — — 0 0.470.23 0.04 0.16 0.03 0.06 0.00 0.05 0.08 0.01 0.00 0.05 0.08 0.08SEQID-02093 406715491 — — 0 0.41 0.21 0.05 0.23 0.02 0.06 0.00 0.03 0.050.05 0.01 0.06 0.08 0.08 SEQID-02094 291568112 — — 0 0.46 0.18 0.06 0.030.05 0.12 0.01 0.03 0.04 0.04 0.03 0.04 0.07 0.09 SEQID-02095 291565897— — 1 0.52 0.24 0.05 0.08 0.03 0.04 0.00 0.03 0.11 0.05 0.02 0.08 0.100.08 SEQID-02096 291568829 — — 0 0.41 0.25 0.08 0.09 0.02 0.09 0.01 0.040.06 0.04 0.01 0.06 0.12 0.03 SEQID-02097 291567800 — — 1 0.46 0.26 0.070.11 0.06 0.02 0.00 0.06 0.07 0.07 0.01 0.06 0.07 0.12 SEQID-02098291567422 — — 0 0.38 0.12 0.07 0.07 0.07 0.05 0.01 0.07 0.08 0.04 0.000.03 0.05 0.11 SEQID-02099 406715501 — — 0 0.48 0.23 0.04 0.10 0.03 0.050.00 0.07 0.08 0.04 0.01 0.10 0.08 0.07 SEQID-02100 406716242 — — 1 0.420.19 0.08 0.06 0.03 0.09 0.00 0.07 0.09 0.01 0.01 0.04 0.11 0.09SEQID-02101 291567386 — — 0 0.43 0.22 0.05 0.08 0.05 0.05 0.00 0.09 0.090.02 0.03 0.08 0.07 0.07 SEQID-02102 406716309 — — 1 0.43 0.16 0.05 0.090.04 0.07 0.00 0.05 0.09 0.04 0.07 0.06 0.04 0.05 SEQID-02103 291565931— — 1 0.48 0.24 0.06 0.08 0.01 0.07 0.01 0.05 0.07 0.04 0.01 0.05 0.120.09 SEQID-02104 291566379 — — 1 0.45 0.21 0.03 0.09 0.03 0.04 0.02 0.050.08 0.03 0.01 0.07 0.09 0.05 SEQID-02105 291571503 — — 0 0.48 0.23 0.060.10 0.02 0.04 0.01 0.05 0.08 0.03 0.00 0.07 0.10 0.09 SEQID-02106406715051 — — 1 0.49 0.24 0.04 0.04 0.05 0.06 0.00 0.08 0.05 0.04 0.010.07 0.10 0.09 SEQID-02107 291566214 — — 1 0.47 0.23 0.03 0.08 0.07 0.060.01 0.04 0.06 0.04 0.04 0.07 0.10 0.05 SEQID-02108 291567878 — — 1 0.460.23 0.07 0.05 0.06 0.07 0.02 0.03 0.09 0.05 0.02 0.08 0.09 0.07SEQID-02109 291572086 — — 1 0.45 0.25 0.05 0.09 0.02 0.08 0.02 0.05 0.070.05 0.03 0.08 0.10 0.05 SEQID-02110 291568830 — — 1 0.46 0.18 0.05 0.050.04 0.07 0.01 0.04 0.07 0.04 0.03 0.05 0.08 0.06 SEQID-02111 291565792— — 1 0.58 0.36 0.07 0.04 0.04 0.04 0.00 0.05 0.04 0.04 0.01 0.12 0.160.03 SEQID-02112 291566578 — — 0 0.43 0.24 0.03 0.10 0.04 0.06 0.01 0.040.11 0.05 0.02 0.06 0.09 0.05 SEQID-02113 291569922 — — 1 0.46 0.27 0.050.09 0.02 0.08 0.00 0.04 0.08 0.05 0.02 0.09 0.10 0.06 SEQID-02114406713771 — — 1 0.42 0.22 0.05 0.08 0.07 0.05 0.01 0.06 0.06 0.05 0.020.06 0.08 0.04 SEQID-02115 291566950 — — 1 0.45 0.22 0.07 0.07 0.04 0.060.02 0.04 0.08 0.05 0.01 0.07 0.09 0.05 SEQID-02116 406712549 — — 1 0.460.24 0.05 0.08 0.04 0.06 0.01 0.04 0.09 0.03 0.03 0.06 0.11 0.06SEQID-02117 17974193 — — 0 0.53 0.19 0.02 0.12 0.04 0.01 0.01 0.08 0.050.04 0.00 0.04 0.07 0.10 SEQID-02118 291569292 — — 0 0.48 0.21 0.06 0.110.03 0.03 0.00 0.04 0.14 0.02 0.00 0.04 0.07 0.14 SEQID-02119 291569856— — 0 0.44 0.28 0.06 0.10 0.02 0.03 0.00 0.02 0.11 0.05 0.02 0.09 0.030.03 SEQID-02120 291569285 — — 0 0.33 0.13 0.04 0.15 0.03 0.07 0.01 0.010.12 0.09 0.00 0.02 0.05 0.05 SEQID-02121 406714138 — — 0 0.47 0.23 0.030.12 0.02 0.05 0.00 0.06 0.11 0.04 0.04 0.08 0.06 0.09 SEQID-02122291570835 — — 1 0.68 0.36 0.03 0.02 0.03 0.02 0.01 0.02 0.08 0.06 0.030.18 0.14 0.04 SEQID-02123 291568903 — — 0 0.39 0.20 0.09 0.11 0.05 0.040.01 0.04 0.05 0.02 0.01 0.02 0.10 0.05 SEQID-02124 291567801 — — 0 0.370.19 0.07 0.15 0.04 0.03 0.01 0.06 0.05 0.08 0.00 0.05 0.10 0.09SEQID-02125 406713989 — — 0 0.41 0.24 0.10 0.07 0.03 0.04 0.00 0.11 0.120.02 0.01 0.10 0.13 0.08 SEQID-02126 291570409 — — 0 0.52 0.23 0.07 0.030.03 0.08 0.00 0.05 0.09 0.05 0.00 0.04 0.12 0.09 SEQID-02127 P13577 — —1 0.40 0.17 0.07 0.21 0.03 0.03 0.00 0.01 0.09 0.02 0.04 0.03 0.06 0.05SEQID-02128 406714844 — — 1 0.45 0.23 0.06 0.07 0.05 0.05 0.02 0.07 0.070.02 0.02 0.06 0.10 0.05 SEQID-02129 406713988 — — 0 0.36 0.25 0.10 0.120.05 0.03 0.00 0.10 0.15 0.03 0.01 0.07 0.14 0.05 SEQID-02130 406713332— — 1 0.49 0.25 0.08 0.05 0.05 0.06 0.00 0.03 0.07 0.06 0.01 0.10 0.060.098 SEQID-02131 406713096 — — 1 0.44 0.23 0.04 0.05 0.05 0.08 0.000.07 0.09 0.04 0.01 0.07 0.09 0.09 SEQID-02132 291571396 — — 1 0.44 0.240.04 0.08 0.05 0.04 0.01 0.05 0.12 0.05 0.03 0.08 0.08 0.04 SEQID-02133406714445 — — 1 0.46 0.22 0.03 0.08 0.05 0.06 0.00 0.07 0.11 0.02 0.000.05 0.11 0.07 SEQID-02134 291566643 — — 0 0.37 0.21 0.05 0.03 0.09 0.130.00 0.05 0.04 0.12 0.00 0.07 0.09 0.01 SEQID-02135 291568361 — — 0 0.440.27 0.06 0.08 0.04 0.07 0.02 0.06 0.06 0.04 0.01 0.06 0.12 0.07SEQID-02136 291568800 — — 1 0.46 0.24 0.07 0.08 0.03 0.08 0.01 0.05 0.070.03 0.03 0.06 0.12 0.04 SEQID-02137 406712435 — — 1 0.44 0.25 0.07 0.040.04 0.05 0.01 0.07 0.08 0.05 0.01 0.06 0.09 0.05 SEQID-02138 291571840— — 0 0.47 0.25 0.05 0.07 0.05 0.06 0.01 0.05 0.08 0.04 0.03 0.06 0.120.05 SEQID-02139 291571996 — — 1 0.45 0.26 0.09 0.05 0.04 0.05 0.01 0.060.10 0.05 0.01 0.06 0.10 0.07 SEQID-02140 406716058 — — 0 0.40 0.19 0.040.12 0.04 0.05 0.02 0.03 0.10 0.07 0.01 0.06 0.08 0.06 SEQID-02141291568019 — — 1 0.43 0.21 0.07 0.10 0.04 0.07 0.01 0.02 0.07 0.04 0.020.06 0.07 0.07 SEQID-02142 291570518 — — 1 0.48 0.23 0.06 0.06 0.04 0.060.02 0.05 0.06 0.04 0.05 0.07 0.11 0.06 SEQID-02143 291566657 — — 1 0.570.38 0.08 0.04 0.03 0.04 0.00 0.02 0.07 0.05 0.00 0.12 0.14 0.02SEQID-02144 406711605 — — 1 0.49 0.27 0.07 0.06 0.04 0.06 0.02 0.04 0.070.05 0.04 0.07 0.10 0.06 SEQID-02145 406713196 — — 1 0.46 0.30 0.06 0.080.04 0.06 0.01 0.05 0.07 0.04 0.02 0.09 0.12 0.05 SEQID-02146 291570777— — 1 0.47 0.21 0.06 0.09 0.04 0.05 0.01 0.04 0.09 0.02 0.04 0.05 0.080.06 SEQID-02147 406712981 — — 1 0.43 0.19 0.03 0.06 0.05 0.04 0.00 0.120.12 0.02 0.02 0.04 0.12 0.06 SEQID-02148 291569312 — — 1 0.40 0.24 0.040.12 0.05 0.07 0.00 0.04 0.10 0.03 0.02 0.07 0.09 0.03 SEQID-02149406713557 — — 1 0.43 0.20 0.05 0.09 0.05 0.07 0.01 0.05 0.08 0.04 0.020.06 0.08 0.06 SEQID-02150 291570203 — — 1 0.41 0.20 0.04 0.05 0.01 0.030.00 0.03 0.07 0.11 0.01 0.05 0.07 0.02 SEQID-02151 291565708 — — 1 0.450.22 0.03 0.07 0.05 0.07 0.00 0.06 0.09 0.03 0.02 0.07 0.10 0.06SEQID-02152 291570064 — — 1 0.46 0.24 0.06 0.07 0.03 0.06 0.01 0.04 0.100.04 0.01 0.08 0.09 0.06 SEQID-02153 291572019 — — 1 0.44 0.24 0.04 0.100.04 0.05 0.01 0.08 0.09 0.02 0.03 0.06 0.12 0.05 SEQID-02154 291568067— — 1 0.37 0.21 0.07 0.05 0.05 0.12 0.00 0.06 0.14 0.03 0.01 0.05 0.110.03 SEQID-02155 291568693 — — 1 0.44 0.22 0.05 0.07 0.05 0.05 0.01 0.070.08 0.03 0.03 0.07 0.10 0.05 SEQID-02156 406713711 — — 0 0.51 0.19 0.040.05 0.05 0.00 0.00 0.06 0.08 0.04 0.00 0.05 0.12 0.04 SEQID-02157406715505 — — 0 0.42 0.24 0.04 0.15 0.04 0.04 0.00 0.09 0.12 0.01 0.050.05 0.18 0.08 SEQID-02158 406715222 — — 1 0.39 0.12 0.03 0.19 0.03 0.060.00 0.00 0.17 0.04 0.03 0.04 0.04 0.098 SEQID-02159 291571965 — — 10.40 0.18 0.05 0.09 0.00 0.07 0.11 0.03 0.06 0.04 0.02 0.05 0.06 0.04SEQID-02160 291570671 — — 0 0.42 0.22 0.06 0.09 0.07 0.04 0.01 0.04 0.090.04 0.00 0.05 0.03 0.09 SEQID-02161 291567416 — — 0 0.44 0.16 0.10 0.070.05 0.03 0.02 0.05 0.11 0.04 0.01 0.05 0.02 0.10 SEQID-02162 157042619— — 0 0.38 0.14 0.02 0.11 0.06 0.04 0.00 0.05 0.11 0.05 0.00 0.07 0.010.05 SEQID-02163 291566338 — — 0 0.41 0.10 0.06 0.10 0.02 0.05 0.00 0.040.08 0.04 0.00 0.02 0.06 0.13 SEQID-02164 291571410 — — 1 0.48 0.24 0.120.04 0.06 0.07 0.02 0.03 0.02 0.05 0.01 0.03 0.11 0.10 SEQID-02165291568589 — — 0 0.48 0.25 0.05 0.04 0.03 0.06 0.02 0.08 0.08 0.03 0.000.05 0.08 0.05 SEQID-02166 P48852 — — 0 0.48 0.24 0.04 0.16 0.01 0.090.02 0.04 0.04 0.01 0.03 0.10 0.09 0.089 SEQID-02167 291567795 — — 00.51 0.21 0.02 0.12 0.03 0.04 0.00 0.04 0.07 0.04 0.03 0.04 0.04 0.15SEQID-02168 291566622 — — 0 0.41 0.22 0.04 0.07 0.04 0.06 0.00 0.08 0.120.07 0.00 0.02 0.14 0.07 SEQID-02169 406713351 — — 0 0.53 0.26 0.05 0.030.04 0.02 0.00 0.05 0.09 0.03 0.00 0.05 0.09 0.09 SEQID-02170 291567797— — 1 0.50 0.23 0.04 0.15 0.04 0.03 0.01 0.03 0.06 0.04 0.02 0.08 0.080.08 SEQID-02171 291565935 — — 0 0.45 0.26 0.03 0.17 0.02 0.02 0.00 0.070.09 0.04 0.01 0.12 0.04 0.08 SEQID-02172 406712927 — — 1 0.48 0.23 0.070.05 0.06 0.05 0.01 0.05 0.06 0.03 0.02 0.05 0.12 0.07 SEQID-02173291569027 — — 1 0.51 0.26 0.07 0.03 0.04 0.03 0.01 0.03 0.13 0.05 0.010.08 0.10 0.09 SEQID-02174 291566287 — — 1 0.47 0.26 0.05 0.06 0.02 0.060.01 0.08 0.07 0.04 0.01 0.06 0.13 0.04 SEQID-02175 406715357 — — 1 0.580.34 0.06 0.04 0.04 0.03 0.00 0.03 0.05 0.04 0.01 0.06 0.17 0.01SEQID-02176 406715137 — — 1 0.46 0.26 0.06 0.04 0.04 0.04 0.01 0.05 0.130.05 0.03 0.07 0.11 0.06 SEQID-02177 406710703 — — 1 0.40 0.15 0.05 0.060.03 0.03 0.02 0.07 0.08 0.06 0.02 0.02 0.07 0.05 SEQID-02178 291570807— — 1 0.61 0.27 0.03 0.05 0.00 0.02 0.01 0.03 0.04 0.04 0.03 0.09 0.090.05 SEQID-02179 291569898 — — 1 0.49 0.26 0.06 0.04 0.03 0.04 0.01 0.070.08 0.04 0.02 0.07 0.11 0.06 SEQID-02180 291570674 — — 1 0.45 0.27 0.080.09 0.06 0.05 0.01 0.03 0.06 0.05 0.02 0.08 0.10 0.02 SEQID-02181291565912 — — 1 0.44 0.23 0.07 0.08 0.04 0.05 0.01 0.08 0.09 0.02 0.010.06 0.10 0.06 SEQID-02182 406714269 — — 1 0.47 0.22 0.03 0.08 0.02 0.050.01 0.06 0.10 0.03 0.02 0.07 0.08 0.06 SEQID-02183 291571644 — — 1 0.480.26 0.05 0.05 0.03 0.07 0.01 0.07 0.05 0.04 0.02 0.10 0.10 0.07SEQID-02184 291567808 — — 1 0.44 0.25 0.06 0.09 0.04 0.08 0.01 0.06 0.100.03 0.02 0.08 0.11 0.06 SEQID-02185 291571141 — — 1 0.45 0.23 0.03 0.080.06 0.07 0.01 0.05 0.06 0.04 0.03 0.08 0.09 0.06 SEQID-02186 406714429— — 1 0.57 0.26 0.08 0.03 0.02 0.04 0.01 0.04 0.04 0.05 0.05 0.05 0.140.03 SEQID-02187 291566376 — — 1 0.46 0.19 0.04 0.05 0.04 0.07 0.01 0.040.07 0.05 0.01 0.05 0.09 0.05 SEQID-02188 291570198 — — 1 0.43 0.17 0.060.09 0.03 0.07 0.02 0.02 0.10 0.04 0.03 0.03 0.06 0.06 SEQID-02189406715783 — — 1 0.50 0.24 0.06 0.06 0.04 0.06 0.01 0.04 0.07 0.04 0.040.07 0.11 0.07 SEQID-02190 291568588 — — 1 0.46 0.26 0.08 0.06 0.03 0.050.02 0.05 0.06 0.06 0.01 0.08 0.09 0.06 SEQID-02191 291569924 — — 1 0.470.23 0.09 0.06 0.03 0.06 0.01 0.04 0.07 0.07 0.02 0.05 0.12 0.06SEQID-02192 406712516 — — 1 0.46 0.24 0.08 0.05 0.04 0.05 0.00 0.06 0.050.04 0.01 0.07 0.08 0.05 SEQID-02193 291568241 — — 0 0.53 0.34 0.07 0.040.03 0.03 0.01 0.04 0.05 0.05 0.00 0.10 0.17 0.03 SEQID-02194 291571841— — 0 0.47 0.30 0.06 0.09 0.04 0.04 0.00 0.06 0.08 0.05 0.00 0.08 0.140.02 SEQID-02195 406712605 — — 1 0.43 0.19 0.06 0.09 0.03 0.05 0.01 0.060.09 0.03 0.01 0.08 0.07 0.05 SEQID-02196 291567555 — — 1 0.54 0.27 0.070.04 0.03 0.03 0.01 0.03 0.05 0.07 0.02 0.10 0.10 0.02 SEQID-02197291569604 — — 1 0.38 0.15 0.07 0.03 0.01 0.08 0.00 0.02 0.20 0.02 0.010.02 0.05 0.08 SEQID-02198 406713974 — — 1 0.41 0.23 0.05 0.04 0.06 0.080.00 0.05 0.05 0.07 0.00 0.05 0.09 0.01 SEQID-02199 291571795 — — 1 0.440.24 0.06 0.07 0.04 0.07 0.00 0.08 0.07 0.04 0.03 0.08 0.11 0.06SEQID-02200 291570843 — — 1 0.43 0.19 0.06 0.07 0.06 0.07 0.01 0.04 0.060.05 0.02 0.08 0.07 0.05 SEQID-02201 291569589 — — 1 0.43 0.22 0.07 0.080.04 0.05 0.01 0.05 0.08 0.05 0.03 0.08 0.07 0.04 SEQID-02202 291569371— — 1 0.46 0.19 0.05 0.08 0.03 0.06 0.01 0.04 0.09 0.05 0.03 0.05 0.070.06 SEQID-02203 291566291 — — 1 0.42 0.19 0.04 0.09 0.04 0.06 0.01 0.050.09 0.04 0.03 0.06 0.09 0.07 SEQID-02204 291568479 — — 1 0.48 0.21 0.030.07 0.04 0.07 0.01 0.05 0.11 0.02 0.03 0.07 0.09 0.07 SEQID-02205291566322 — — 1 0.45 0.22 0.04 0.09 0.03 0.06 0.00 0.08 0.09 0.03 0.020.06 0.10 0.05 SEQID-02206 291567103 — — 1 0.50 0.29 0.06 0.06 0.04 0.060.01 0.06 0.06 0.04 0.01 0.10 0.11 0.04 SEQID-02207 I3JEK7 — — 1 0.460.20 0.04 0.07 0.03 0.07 0.02 0.03 0.10 0.03 0.02 0.06 0.06 0.09SEQID-02208 I3KK23 — — 1 0.47 0.18 0.05 0.05 0.05 0.07 0.01 0.05 0.060.02 0.04 0.05 0.08 0.13 SEQID-02209 I3JYT9 — — 1 0.45 0.19 0.05 0.070.04 0.05 0.01 0.07 0.15 0.02 0.02 0.04 0.10 0.12 SEQID-02210 I3IZY8 — —1 0.44 0.18 0.06 0.07 0.04 0.05 0.01 0.07 0.13 0.02 0.03 0.04 0.09 0.11SEQID-02211 I3KLJ9 — — 1 0.47 0.20 0.04 0.06 0.03 0.05 0.02 0.04 0.120.03 0.02 0.06 0.07 0.11 SEQID-02212 I3IZU1 — — 1 0.46 0.19 0.06 0.070.04 0.05 0.01 0.07 0.14 0.02 0.02 0.05 0.09 0.11 SEQID-02213 I3K022 — —1 0.49 0.24 0.06 0.06 0.04 0.06 0.03 0.02 0.09 0.03 0.01 0.07 0.09 0.07SEQID-02214 I3IZY3 — — 1 0.40 0.18 0.06 0.10 0.04 0.06 0.00 0.10 0.180.02 0.02 0.03 0.10 0.12 SEQID-02215 I3K5K1 — — 1 0.46 0.20 0.05 0.080.05 0.06 0.01 0.06 0.11 0.02 0.03 0.07 0.09 0.07 SEQID-02216 I3IUB3 — —1 0.47 0.19 0.05 0.06 0.03 0.05 0.01 0.03 0.08 0.03 0.04 0.04 0.06 0.09SEQID-02217 I3KK81 — — 1 0.46 0.20 0.05 0.07 0.03 0.06 0.01 0.03 0.080.04 0.03 0.08 0.07 0.06 SEQID-02218 I3IZX8 — — 1 0.51 0.19 0.05 0.040.05 0.05 0.01 0.05 0.09 0.03 0.03 0.07 0.07 0.10 SEQID-02219 I3KU01 — —1 0.45 0.19 0.05 0.07 0.04 0.05 0.01 0.07 0.15 0.02 0.03 0.05 0.11 0.12SEQID-02220 I3JT59 — — 1 0.45 0.18 0.05 0.07 0.04 0.05 0.01 0.07 0.140.02 0.02 0.05 0.10 0.12 SEQID-02221 I3IZY5 — — 1 0.49 0.20 0.05 0.050.05 0.05 0.01 0.04 0.08 0.03 0.02 0.07 0.08 0.08 SEQID-02222 I3KZL6 — —1 0.45 0.18 0.05 0.07 0.05 0.05 0.01 0.07 0.15 0.02 0.02 0.04 0.11 0.12SEQID-02223 I3KXM4 — — 1 0.48 0.23 0.04 0.06 0.05 0.05 0.01 0.03 0.090.04 0.01 0.06 0.07 0.09 SEQID-02224 I3JDJ0 — — 1 0.47 0.19 0.05 0.060.03 0.05 0.02 0.03 0.08 0.04 0.03 0.06 0.06 0.09 SEQID-02225 I3JDJ1 — —1 0.47 0.19 0.05 0.06 0.04 0.05 0.01 0.03 0.08 0.04 0.03 0.06 0.06 0.08SEQID-02226 I3KFP0 — — 1 0.50 0.20 0.02 0.07 0.05 0.07 0.01 0.03 0.090.05 0.05 0.04 0.09 0.09 SEQID-02227 I3JE80 — — 1 0.48 0.22 0.04 0.060.04 0.06 0.02 0.04 0.10 0.03 0.03 0.05 0.11 0.07 SEQID-02228 I3KW15 — —1 0.45 0.21 0.07 0.06 0.05 0.04 0.02 0.05 0.07 0.04 0.03 0.05 0.09 0.08SEQID-02229 I3KvU7 — — 1 0.48 0.20 0.04 0.06 0.04 0.07 0.02 0.02 0.100.03 0.02 0.06 0.06 0.11 SEQID-02230 I3JBN0 — — 1 0.46 0.20 0.05 0.090.06 0.06 0.01 0.04 0.09 0.03 0.04 0.06 0.08 0.07 SEQID-02231 I3K556 — —1 0.52 0.22 0.06 0.05 0.05 0.06 0.01 0.01 0.06 0.05 0.04 0.07 0.05 0.10SEQID-02232 I3J7R3 — — 1 0.47 0.21 0.04 0.07 0.04 0.06 0.02 0.04 0.110.03 0.03 0.05 0.10 0.07 SEQID-02233 I3JS50 — — 1 0.47 0.18 0.04 0.070.05 0.06 0.01 0.04 0.08 0.02 0.04 0.05 0.09 0.08 SEQID-02234 I3JKR2 — —1 0.49 0.22 0.06 0.05 0.05 0.07 0.01 0.03 0.08 0.04 0.03 0.07 0.08 0.11SEQID-02235 I3JL13 — — 1 0.49 0.21 0.02 0.08 0.04 0.07 0.01 0.04 0.090.05 0.04 0.04 0.10 0.09 SEQID-02236 I3JRU6 — — 1 0.48 0.20 0.04 0.060.04 0.05 0.01 0.03 0.10 0.04 0.03 0.04 0.06 0.09 SEQID-02237 I3JS33 — —1 0.47 0.18 0.04 0.12 0.03 0.05 0.02 0.05 0.07 0.04 0.04 0.06 0.07 0.08SEQID-02238 I3JXH7 — — 1 0.42 0.13 0.05 0.15 0.01 0.06 0.00 0.05 0.190.01 0.03 0.04 0.07 0.19 SEQID-02239 I3JU24 — — 1 0.47 0.18 0.06 0.040.05 0.07 0.01 0.05 0.12 0.03 0.01 0.07 0.07 0.11 SEQID-02240 I3JFQ4 — —1 0.46 0.20 0.04 0.07 0.04 0.06 0.02 0.03 0.09 0.04 0.02 0.05 0.07 0.08SEQID-02241 I3K6V3 — — 0 0.46 0.21 0.05 0.04 0.06 0.09 0.01 0.05 0.090.04 0.03 0.04 0.11 0.07 SEQID-02242 I3IXG2 — — 1 0.45 0.16 0.03 0.050.04 0.04 0.01 0.04 0.10 0.07 0.03 0.04 0.07 0.11 SEQID-02243 I3J8Q1 — —1 0.38 0.17 0.05 0.11 0.04 0.06 0.00 0.08 0.13 0.02 0.02 0.05 0.09 0.06SEQID-02244 I3JXH4 — — 1 0.26 0.10 0.08 0.09 0.04 0.04 0.01 0.03 0.060.16 0.02 0.02 0.05 0.05 SEQID-02245 I3J8X4 — — 0 0.40 0.18 0.11 0.050.07 0.07 0.00 0.03 0.11 0.04 0.01 0.05 0.07 0.09 SEQID-02246 I3KFU1 — —1 0.45 0.18 0.07 0.05 0.04 0.05 0.00 0.07 0.06 0.05 0.04 0.07 0.06 0.08SEQID-02247 I3KSF9 — — 1 0.50 0.22 0.06 0.08 0.04 0.05 0.02 0.04 0.060.05 0.03 0.06 0.09 0.06 SEQID-02248 I3JGN1 — — 1 0.26 0.09 0.08 0.080.02 0.06 0.02 0.04 0.07 0.15 0.01 0.02 0.04 0.05 SEQID-02249 I3JMB4 — —1 0.25 0.09 0.07 0.08 0.02 0.06 0.01 0.04 0.06 0.16 0.01 0.03 0.04 0.05SEQID-02250 I3KBQ8 — — 1 0.45 0.17 0.07 0.06 0.03 0.06 0.01 0.02 0.110.07 0.02 0.06 0.05 0.11 SEQID-02251 I3KB11 — — 1 0.57 0.28 0.09 0.030.04 0.05 0.01 0.03 0.07 0.05 0.05 0.06 0.10 0.10 SEQID-02252 I3KBN9 — —1 0.44 0.18 0.07 0.05 0.04 0.05 0.02 0.03 0.10 0.03 0.01 0.06 0.05 0.12SEQID-02253 I3JNZ0 — — 1 0.48 0.23 0.06 0.08 0.03 0.06 0.02 0.03 0.080.04 0.03 0.08 0.07 0.09 SEQID-02254 I3JXF9 — — 1 0.53 0.21 0.06 0.060.03 0.08 0.01 0.04 0.10 0.01 0.03 0.05 0.10 0.19 SEQID-02255 I3KMQ5 — —1 0.41 0.14 0.04 0.13 0.03 0.07 0.00 0.07 0.07 0.04 0.03 0.04 0.06 0.06SEQID-02256 I3JQE5 — — 1 0.49 0.21 0.05 0.05 0.04 0.08 0.01 0.04 0.060.05 0.03 0.08 0.07 0.08 SEQID-02257 I3K5C3 — — 1 0.51 0.23 0.06 0.040.05 0.06 0.02 0.04 0.08 0.06 0.02 0.07 0.06 0.11 SEQID-02258 I3KL70 — —0 0.42 0.18 0.05 0.11 0.03 0.05 0.00 0.05 0.14 0.04 0.01 0.03 0.07 0.11SEQID-02259 I3KER1 — — 1 0.42 0.20 0.03 0.02 0.02 0.25 0.00 0.02 0.110.02 0.04 0.05 0.08 0.05 SEQID-02260 I3KOM4 — — 0 0.48 0.25 0.04 0.070.01 0.09 0.01 0.04 0.09 0.05 0.01 0.07 0.10 0.14 SEQID-02261 I3J820 — —1 0.50 0.20 0.06 0.08 0.04 0.04 0.01 0.03 0.10 0.04 0.04 0.07 0.08 0.10SEQID-02262 I3KM40 — — 1 0.52 0.20 0.07 0.07 0.03 0.05 0.02 0.04 0.030.05 0.01 0.09 0.06 0.10 SEQID-02263 I3K3X8 — — 1 0.46 0.19 0.06 0.080.04 0.05 0.04 0.06 0.08 0.03 0.06 0.04 0.09 0.08 SEQID-02264 I3IZI3 — —0 0.42 0.17 0.03 0.06 0.03 0.13 0.01 0.03 0.17 0.04 0.00 0.06 0.08 0.06SEQID-02265 I3IU19 — — 1 0.48 0.20 0.05 0.07 0.04 0.08 0.03 0.04 0.090.03 0.02 0.07 0.08 0.10 SEQID-02266 I3IY11 — — 1 0.50 0.21 0.05 0.060.05 0.05 0.01 0.03 0.089 0.05 0.03 0.08 0.06 0.12 SEQID-02267 I3KXA2 —— 1 0.45 0.20 0.04 0.06 0.04 0.05 0.02 0.02 0.09 0.03 0.02 0.06 0.060.08 SEQID-02268 I3K8C6 — — 1 0.51 0.22 0.05 0.07 0.04 0.04 0.01 0.030.05 0.04 0.04 0.06 0.10 0.05 SEQID-02269 I3IZN6 — — 1 0.46 0.20 0.040.08 0.04 0.06 0.02 0.04 0.07 0.04 0.04 0.04 0.10 0.05 SEQID-02270I3JPF4 — — 1 0.46 0.20 0.04 0.05 0.04 0.07 0.01 0.03 0.07 0.06 0.03 0.060.05 0.09 SEQID-02271 I3JTN2 — — 1 0.44 0.20 0.04 0.05 0.04 0.07 0.010.08 0.11 0.02 0.03 0.05 0.11 0.08 SEQID-02272 P60713 — — 1 0.47 0.200.05 0.07 0.02 0.06 0.01 0.04 0.08 0.04 0.03 0.08 0.07 0.06 SEQID-02273O138751 — — 1 0.46 0.21 0.05 0.10 0.05 0.06 0.01 0.04 0.09 0.03 0.030.06 0.09 0.06 SEQID-02274 P14639 — — 1 0.46 0.18 0.05 0.06 0.02 0.070.06 0.04 0.10 0.01 0.04 0.02 0.11 0.11 SEQID-02275 B2MVW8 — — 1 0.500.21 0.07 0.08 0.03 0.05 0.01 0.05 0.02 0.05 0.01 0.07 0.08 0.09SEQID-02276 D7R7V6 — — 1 0.53 0.22 0.06 0.04 0.06 0.06 0.01 0.02 0.050.05 0.04 0.07 0.06 0.09 SEQID-02277 C8BKC8 — — 1 0.47 0.12 0.04 0.040.05 0.05 0.10 0.05 0.04 0.03 0.06 0.02 0.03 0.14 SEQID-02278 B7U168 — —1 0.47 0.20 0.07 0.07 0.02 0.03 0.02 0.04 0.06 0.04 0.02 0.03 0.09 0.08SEQID-02279 B9VGZ8 — — 1 0.47 0.16 0.06 0.06 0.05 0.08 0.01 0.05 0.100.04 0.01 0.06 0.05 0.10 SEQID-02280 Q9N116 — — 1 0.43 0.23 0.05 0.080.05 0.06 0.03 0.06 0.08 0.05 0.02 0.07 0.08 0.08 SEQID-02281 Q9BE42 — —0 0.50 0.168 0.06 0.05 0.01 0.08 0.00 0.04 0.15 0.02 0.02 0.02 0.08 0.12SEQID-02282 B2LU28 — — 0 0.40 0.18 0.08 0.07 0.02 0.08 0.00 0.05 0.220.00 0.01 0.04 0.11 0.15 SEQID-02283 Q9N109 — — 0 0.53 0.30 0.05 0.060.06 0.06 0.01 0.07 0.07 0.03 0.02 0.09 0.12 0.09 SEQID-02284 Q9BE43 — —0 0.49 0.14 0.07 0.04 0.02 0.06 0.00 0.04 0.12 0.03 0.02 0.03 0.03 0.12SEQID-02285 Q9BE44 — — 0 0.50 0.15 0.06 0.04 0.02 0.05 0.00 0.04 0.140.03 0.02 0.03 0.04 0.12 SEQID-02286 Q9N113 — — 0 0.44 0.19 0.08 0.040.06 0.08 0.00 0.02 0.09 0.05 0.03 0.06 0.08 0.10 SEQID-02287 P68240 — —0 0.56 0.23 0.08 0.03 0.04 0.07 0.01 0.01 0.03 0.04 0.08 0.00 0.15 0.09SEQID-02288 Q1A2D1 — — 0 0.55 0.23 0.07 0.06 0.06 0.06 0.01 0.03 0.060.04 0.08 0.00 0.12 0.08 SEQID-02289 Q9N104 — — 0 0.52 0.27 0.09 0.030.06 0.04 0.03 0.05 0.05 0.04 0.03 0.10 0.07 0.07 SEQID-02290 B6VCA9 — —0 0.50 0.16 0.05 0.04 0.06 0.08 0.00 0.05 0.12 0.03 0.01 0.05 0.06 0.12SEQID-02291 B9VGZ5 — — 1 0.57 0.32 0.05 0.05 0.03 0.05 0.00 0.04 0.050.03 0.02 0.098 0.15 0.10 SEQID-02292 Q7YS10 — — 0 0.57 0.28 0.03 0.000.03 0.05 0.02 0.09 0.12 0.04 0.03 0.08 0.13 0.12 SEQID-02293 P79395 — —0 0.45 0.19 0.02 0.06 0.07 0.02 0.00 0.02 0.08 0.02 0.04 0.04 0.06 0.10SEQID-02294 B0FZM4 — — 0 0.47 0.21 0.03 0.05 0.06 0.06 0.01 0.04 0.140.05 0.03 0.02 0.10 0.07 SEQID-02295 C5IJA8 — — 0 0.48 0.22 0.03 0.090.02 0.05 0.01 0.04 0.11 0.05 0.01 0.05 0.09 0.11 SEQID-02296 B2MVX2 — —1 0.51 0.22 0.06 0.09 0.03 0.03 0.01 0.04 0.04 0.06 0.01 0.04 0.11 0.06SEQID-02297 H2DGR2 — — 1 0.45 0.21 0.06 0.08 0.05 0.07 0.01 0.05 0.090.04 0.02 0.07 0.08 0.09 SEQID-02298 B0LRN3 — — 0 0.41 0.19 0.08 0.180.01 0.03 0.01 0.07 0.06 0.03 0.02 0.06 0.09 0.10 SEQID-02299 Q35331 — —1 0.44 0.25 0.08 0.11 0.02 0.05 0.02 0.05 0.09 0.05 0.02 0.07 0.08 0.06SEQID-02300 B2LSM3 — — 1 0.38 0.16 0.06 0.12 0.04 0.05 0.01 0.07 0.070.04 0.04 0.05 0.07 0.04 SEQID-02301 B6E3I6 — — 1 0.54 0.19 0.03 0.050.06 0.06 0.01 0.05 0.07 0.03 0.04 0.05 0.11 0.07 SEQID-02302 Q9N102 — —1 0.47 0.16 0.06 0.06 0.05 0.06 0.03 0.05 0.04 0.04 0.03 0.05 0.05 0.08SEQID-02303 Q5ENY9 — — 1 0.48 0.19 0.03 0.11 0.01 0.06 0.00 0.02 0.090.02 0.06 0.06 0.08 0.06 SEQID-02304 O78750 — — 1 0.56 0.27 0.02 0.040.02 0.04 0.01 0.03 0.07 0.02 0.03 0.08 0.14 0.03 SEQID-02305 P29361 — —1 0.39 0.18 0.06 0.07 0.04 0.06 0.01 0.06 0.14 0.02 0.00 0.04 0.10 0.09SEQID-02306 Q00555 — — 1 0.53 0.26 0.03 0.08 0.04 0.04 0.01 0.05 0.060.03 0.02 0.08 0.13 0.07 SEQID-02307 B7U9A4 — — 1 0.45 0.25 0.06 0.080.02 0.05 0.02 0.06 0.07 0.02 0.03 0.04 0.14 0.04 SEQID-02308 Q9M4M9 — —1 0.44 0.22 0.07 0.06 0.05 0.04 0.02 0.05 0.09 0.05 0.01 0.05 0.11 0.09SEQID-02309 Q02096 — — 1 0.47 0.21 0.03 0.05 0.06 0.07 0.03 0.03 0.050.05 0.03 0.08 0.07 0.07 SEQID-02310 P19464 — — 1 0.50 0.21 0.05 0.050.05 0.06 0.01 0.03 0.12 0.03 0.03 0.03 0.10 0.09 SEQID-02311 P24465 — —1 0.52 0.26 0.04 0.08 0.04 0.05 0.01 0.02 0.09 0.03 0.04 0.06 0.14 0.07SEQID-02312 Q7M224 — — 1 0.47 0.20 0.06 0.06 0.04 0.04 0.00 0.05 0.140.03 0.02 0.02 0.07 0.11 SEQID-02313 Q9SEK6 — — 1 0.47 0.19 0.04 0.080.02 0.06 0.01 0.04 0.10 0.02 0.03 0.05 0.09 0.08 SEQID-02314 Q9M4M7 — —1 0.48 0.22 0.04 0.05 0.05 0.06 0.02 0.04 0.06 0.05 0.04 0.05 0.08 0.06SEQID-02315 P93680 — — 1 0.37 0.16 0.07 0.05 0.06 0.04 0.05 0.05 0.020.07 0.01 0.05 0.07 0.04 SEQID-02316 Q9M7I8 — — 1 0.54 0.21 0.06 0.020.02 0.07 0.02 0.03 0.08 0.03 0.06 0.04 0.11 0.10 SEQID-02317 B0FGG5 — —1 0.47 0.22 0.06 0.05 0.03 0.05 0.01 0.02 0.09 0.05 0.03 0.07 0.07 0.09SEQID-02318 Q68YT2 — — 0 0.44 0.06 0.02 0.00 0.04 0.10 0.00 0.13 0.090.10 0.10 0.03 0.01 0.21 SEQID-02319 P48686 — — 1 0.46 0.19 0.06 0.080.03 0.06 0.02 0.03 0.08 0.05 0.04 0.04 0.09 0.06 SEQID-02320 A7XB47 — —1 0.52 0.22 0.06 0.05 0.03 0.06 0.02 0.04 0.08 0.04 0.03 0.07 0.09 0.09SEQID-02321 Q6DV58 — — 1 0.45 0.17 0.06 0.05 0.02 0.05 0.01 0.05 0.080.05 0.01 0.03 0.07 0.10 SEQID-02322 Q8GTA0 — — 1 0.48 0.17 0.05 0.070.03 0.04 0.06 0.02 0.03 0.05 0.10 0.02 0.10 0.03 SEQID-02323 H6TDM4 — —1 0.45 0.18 0.06 0.07 0.02 0.07 0.02 0.04 0.09 0.04 0.05 0.04 0.11 0.07SEQID-02324 Q9SE87 — — 1 0.48 0.25 0.03 0.11 0.03 0.07 0.01 0.08 0.060.03 0.02 0.06 0.10 0.06 SEQID-02325 F8U7Z9 — — 1 0.42 0.17 0.04 0.070.05 0.05 0.02 0.06 0.10 0.04 0.02 0.04 0.07 0.04 SEQID-02326 A7YX85 — —1 0.47 0.21 0.04 0.08 0.03 0.07 0.01 0.03 0.09 0.03 0.03 0.05 0.11 0.07SEQID-02327 O82795 — — 1 0.52 0.23 0.06 0.04 0.04 0.04 0.01 0.03 0.050.04 0.01 0.07 0.09 0.08 SEQID-02328 Q50DJU7 — — 1 0.49 0.23 0.04 0.070.02 0.07 0.02 0.05 0.08 0.03 0.03 0.07 0.11 0.06 SEQID-02329 Q3HYA1 — —1 0.50 0.21 0.04 0.04 0.04 0.04 0.01 0.03 0.08 0.04 0.02 0.05 0.10 0.07SEQID-02330 Q39366 — — 1 0.46 0.21 0.03 0.08 0.04 0.06 0.01 0.03 0.100.05 0.01 0.05 0.08 0.08 SEQID-02331 Q6PY61 — — 0 0.55 0.10 0.02 0.000.02 0.13 0.00 0.01 0.12 0.07 0.18 0.08 0.01 0.26 SEQID-02332 P09678 — —0 0.49 0.21 0.06 0.04 0.07 0.068 0.01 0.02 0.03 0.11 0.08 0.07 0.07 0.03SEQID-02333 Q944W6 — — 1 0.52 0.21 0.03 0.01 0.02 0.07 0.01 0.03 0.130.04 0.01 0.05 0.09 0.12 SEQID-02334 Q6ZZ92 — — 1 0.47 0.20 0.06 0.070.04 0.06 0.01 0.03 0.03 0.06 0.00 0.05 0.11 0.10 SEQID-02335 D9I762 — —1 0.44 0.22 0.06 0.09 0.04 0.05 0.02 0.03 0.09 0.04 0.03 0.07 0.07 0.06SEQID-02336 I3Y171 — — 1 0.47 0.21 0.06 0.09 0.05 0.07 0.01 0.02 0.100.02 0.03 0.03 0.12 0.09 SEQID-02337 Q4TU02 — — 1 0.46 0.16 0.04 0.050.04 0.07 0.00 0.04 0.07 0.07 0.03 0.03 0.05 0.08 SEQID-02338 Q75UU6 — —1 0.47 0.21 0.07 0.04 0.02 0.06 0.01 0.02 0.08 0.06 0.01 0.06 0.08 0.10SEQID-02339 O82549 — — 1 0.46 0.20 0.04 0.08 0.03 0.08 0.01 0.05 0.070.04 0.05 0.08 0.07 0.06 SEQID-02340 P56294 — — 0 0.42 0.25 0.07 0.080.03 0.05 0.00 0.08 0.08 0.04 0.01 0.08 0.10 0.06 SEQID-02341 P56307 — —1 0.51 0.21 0.06 0.08 0.03 0.05 0.01 0.03 0.05 0.06 0.03 0.05 0.09 0.03SEQID-02342 P56308 — — 1 0.52 0.22 0.05 0.06 0.04 0.03 0.01 0.02 0.050.07 0.04 0.06 0.10 0.03 SEQID-02343 P56319 — — 1 0.55 0.21 0.06 0.060.04 0.03 0.01 0.04 0.05 0.05 0.03 0.05 0.11 0.02 SEQID-02344 P56341 — —1 0.56 0.23 0.06 0.04 0.04 0.04 0.00 0.05 0.03 0.05 0.07 0.07 0.11 0.03SEQID-02345 P56342 — — 1 0.55 0.22 0.06 0.04 0.03 0.04 0.01 0.05 0.030.05 0.07 0.06 0.12 0.02 SEQID-02346 Q8JIV4 — — 0 0.39 0.17 0.06 0.110.03 0.06 0.01 0.08 0.18 0.02 0.02 0.02 0.10 0.13 SEQID-02347 Q8JJ07 — —1 0.43 0.13 0.03 0.13 0.03 0.08 0.00 0.05 0.17 0.02 0.03 0.04 0.07 0.19SEQID-02348 Q98557 — — 1 0.51 0.21 0.03 0.09 0.04 0.06 0.01 0.04 0.080.05 0.04 0.04 0.10 0.09 SEQID-02349 Q8AWX8 — — 1 0.51 0.23 0.06 0.050.05 0.07 0.01 0.02 0.06 0.05 0.04 0.08 0.05 0.09 SEQID-02350 A7XA06 — —1 0.50 0.19 0.02 0.08 0.05 0.07 0.02 0.02 0.08 0.04 0.06 0.04 0.11 0.08SEQID-02351 Q98954 — — 1 0.53 0.21 0.04 0.02 0.06 0.06 0.01 0.07 0.080.03 0.04 0.09 0.08 0.08 SEQID-02352 Q98559 — — 0 0.39 0.16 0.06 0.090.05 0.06 0.01 0.10 0.15 0.01 0.03 0.03 0.10 0.13 SEQID-02353 A7XA16 — —1 0.48 0.24 0.04 0.08 0.04 0.06 0.02 0.03 0.07 0.04 0.01 0.06 0.07 0.08SEQID-02354 Q8QG69 — — 1 0.49 0.17 0.10 0.07 0.02 0.09 0.01 0.03 0.100.02 0.04 0.04 0.10 0.16 SEQID-02355 A5I873 — — 0 0.49 0.18 0.14 0.010.00 0.11 0.03 0.02 0.09 0.04 0.00 0.05 0.08 0.13 SEQID-02356 A7XA17 — —1 0.43 0.17 0.04 0.089 0.06 0.05 0.02 0.03 0.07 0.04 0.02 0.08 0.03 0.06SEQID-02357 A8CZC9 — — 1 0.51 0.22 0.05 0.05 0.04 0.06 0.01 0.03 0.070.05 0.03 0.08 0.06 0.12 SEQID-02358 Q5XQ56 — — 0 0.44 0.21 0.12 0.060.01 0.07 0.00 0.07 0.06 0.03 0.05 0.04 0.11 0.06 SEQID-02359 Q92079 — —1 0.44 0.19 0.07 0.04 0.03 0.06 0.04 0.04 0.05 0.06 0.02 0.05 0.07 0.08SEQID-02360 O98734 — — 1 0.41 0.17 0.04 0.08 0.04 0.07 0.01 0.03 0.070.04 0.03 0.07 0.07 0.05 SEQID-02361 F22AL7 — — 0 0.38 0.23 0.10 0.080.05 0.08 0.04 0.01 0.04 0.04 0.00 0.06 0.09 0.05 SEQID-02362 F22AL8 — —1 0.36 0.18 0.10 0.09 0.05 0.07 0.02 0.03 0.07 0.04 0.02 0.03 0.08 0.05SEQID-02363 I2FJT9 — — 0 0.40 0.23 0.10 0.09 0.07 0.07 0.02 0.05 0.050.03 0.00 0.03 0.11 0.04 SEQID-02364 Q9IHF8 — — 1 0.46 0.21 0.06 0.070.04 0.06 0.01 0.05 0.07 0.05 0.03 0.06 0.08 0.05 SEQID-02365 I2FJU0 — —1 0.38 0.18 0.09 0.06 0.05 0.03 0.01 0.05 0.07 0.04 0.01 0.06 0.08 0.04SEQID-02366 O98733 — — 1 0.49 0.24 0.06 0.06 0.06 0.02 0.01 0.03 0.060.05 0.03 0.08 0.10 0.00 SEQID-02367 Q6TNX3 — — 1 0.56 0.23 0.06 0.030.04 0.04 0.00 0.04 0.03 0.06 0.08 0.06 0.13 0.04 SEQID-02368 B3RG69 — —1 0.58 0.24 0.05 0.03 0.05 0.03 0.01 0.04 0.03 0.05 0.08 0.08 0.11 0.03SEQID-02369 P84527 — — 1 0.36 0.15 0.03 0.06 0.08 0.09 0.07 0.03 0.040.07 0.04 0.05 0.04 0.06 SEQID-02370 P81370 — — 0 0.41 0.14 0.05 0.060.09 0.06 0.07 0.05 0.02 0.06 0.00 0.04 0.07 0.05 SEQID-02371 A5HII1 — —1 0.42 0.18 0.04 0.05 0.07 0.05 0.02 0.04 0.07 0.05 0.01 0.06 0.06 0.05SEQID-02372 Q6TPK4 — — 1 0.48 0.27 0.08 0.07 0.05 0.04 0.00 0.06 0.050.04 0.02 0.02 0.12 0.06 SEQID-02373 P85524 — — 1 0.58 0.26 0.01 0.020.03 0.07 0.01 0.02 0.13 0.03 0.02 0.10 0.07 0.10 SEQID-02374 P85076 — —1 0.47 0.20 0.06 0.05 0.06 0.06 0.01 0.04 0.04 0.04 0.01 0.06 0.06 0.06SEQID-02375 A5HII4 — — 1 0.44 0.20 0.03 0.05 0.08 0.06 0.02 0.03 0.060.05 0.01 0.06 0.07 0.08 SEQID-02376 P43394 — — 1 0.44 0.25 0.04 0.100.03 0.05 0.00 0.04 0.06 0.03 0.04 0.07 0.10 0.03 SEQID-02377 Q06AW1 — —1 0.39 0.19 0.04 0.11 0.05 0.04 0.01 0.08 0.09 0.04 0.04 0.06 0.08 0.03SEQID-02378 Q06AW2 — — 1 0.38 0.19 0.04 0.12 0.05 0.03 0.01 0.08 0.090.05 0.03 0.06 0.09 0.03 SEQID-02379 Q9IB39 — — 0 0.41 0.17 0.10 0.040.05 0.07 0.00 0.04 0.12 0.03 0.01 0.04 0.06 0.10 SEQID-02380 Q9IB37 — —1 0.47 0.18 0.06 0.04 0.05 0.07 0.01 0.04 0.13 0.03 0.01 0.07 0.07 0.10SEQID-02381 Q78CT4 — — 0 0.41 0.18 0.07 0.07 0.02 0.08 0.00 0.05 0.230.01 0.01 0.04 0.12 0.15 SEQID-02382 B9WPP3 — — 1 0.50 0.21 0.05 0.050.05 0.05 0.00 0.03 0.08 0.05 0.03 0.06 0.07 0.09 SEQID-02383 P02074 — —0 0.54 0.25 0.08 0.06 0.05 0.05 0.01 0.02 0.07 0.05 0.06 0.00 0.13 0.07SEQID-02384 G3URG5 — — 1 0.45 0.19 0.05 0.08 0.04 0.04 0.01 0.07 0.140.02 0.03 0.06 0.10 0.11 SEQID-02385 G3UV20 — — 1 0.47 0.19 0.05 0.080.04 0.05 0.01 0.08 0.13 0.02 0.03 0.05 0.10 0.12 SEQID-02386 G1MUC5 — —1 0.48 0.19 0.05 0.06 0.05 0.04 0.01 0.05 0.09 0.03 0.03 0.06 0.08 0.10SEQID-02387 G3US01 — — 0 0.40 0.20 0.06 0.10 0.04 0.05 0.00 0.09 0.190.01 0.03 0.05 0.11 0.12 SEQID-02388 G1MSQ0 — — 1 0.44 0.19 0.05 0.070.05 0.06 0.01 0.08 0.14 0.02 0.03 0.04 0.11 0.12 SEQID-02389 G1NIB8 — —1 0.46 0.20 0.05 0.07 0.03 0.06 0.01 0.03 0.09 0.04 0.03 0.09 0.07 0.06SEQID-02390 G1NNJ7 — — 1 0.45 0.19 0.05 0.08 0.04 0.06 0.01 0.07 0.150.02 0.02 0.04 0.11 0.12 SEQID-02391 G1MS62 — — 1 0.44 0.19 0.06 0.080.05 0.05 0.01 0.07 0.15 0.02 0.02 0.04 0.11 0.12 SEQID-02392 G1MUV8 — —1 0.45 0.19 0.05 0.08 0.04 0.06 0.01 0.07 0.14 0.02 0.02 0.05 0.11 0.12SEQID-02393 G1MT49 — — 1 0.52 0.21 0.04 0.06 0.08 0.03 0.01 0.05 0.070.03 0.03 0.06 0.10 0.10 SEQID-02394 G1NMR6 — — 1 0.52 0.22 0.07 0.050.05 0.07 0.01 0.02 0.04 0.05 0.04 0.06 0.06 0.09 SEQID-02395 G3URH1 — —0 0.39 0.20 0.06 0.12 0.04 0.06 0.00 0.09 0.17 0.01 0.02 0.05 0.11 0.11SEQID-02396 G1MSA4 — — 1 0.49 0.22 0.07 0.09 0.03 0.07 0.01 0.03 0.080.04 0.04 0.07 0.07 0.08 SEQID-02397 G1NGT5 — — 1 0.44 0.19 0.05 0.090.05 0.06 0.01 0.07 0.11 0.02 0.03 0.07 0.09 0.07 SEQID-02398 G1NAX6 — —1 0.48 0.21 0.04 0.06 0.03 0.06 0.01 0.03 0.13 0.03 0.02 0.07 0.07 0.12SEQID-02399 G1N679 — — 1 0.57 0.28 0.04 0.04 0.03 0.06 0.01 0.02 0.060.04 0.07 0.08 0.10 0.10 SEQID-02400 G1NAN1 — — 1 0.47 0.21 0.04 0.060.03 0.05 0.02 0.04 0.11 0.03 0.03 0.06 0.07 0.10 SEQID-02401 G1NS52 — —1 0.47 0.20 0.05 0.07 0.02 0.06 0.01 0.04 0.09 0.04 0.03 0.089 0.07 0.06SEQID-02402 G1NAX9 — — 1 0.47 0.20 0.04 0.04 0.03 0.04 0.02 0.04 0.120.03 0.02 0.05 0.06 0.11 SEQID-02403 G1NJG2 — — 1 0.47 0.18 0.04 0.060.04 0.07 0.01 0.05 0.07 0.02 0.04 0.05 0.08 0.12 SEQID-02404 G3UPH8 — —1 0.46 0.20 0.04 0.07 0.04 0.06 0.02 0.03 0.10 0.03 0.04 0.05 0.07 0.08SEQID-02405 G3UV10 — — 1 0.49 0.18 0.05 0.05 0.03 0.05 0.02 0.04 0.060.04 0.02 0.12 0.04 0.08 SEQID-02406 G1N3D3 — — 1 0.54 0.23 0.06 0.030.05 0.06 0.02 0.02 0.08 0.05 0.03 0.06 0.09 0.12 SEQID-02407 G1NJH3 — —1 0.46 0.17 0.06 0.07 0.04 0.09 0.01 0.05 0.06 0.01 0.05 0.06 0.08 0.12SEQID-02408 G1NJH4 — — 1 0.46 0.16 0.05 0.05 0.04 0.08 0.00 0.06 0.060.01 0.04 0.05 0.07 0.14 SEQID-02409 H9H166 — — 1 0.50 0.22 0.05 0.090.04 0.05 0.02 0.02 0.08 0.05 0.04 0.07 0.09 0.07 SEQID-02410 G1NGV6 — —1 0.48 0.21 0.06 0.07 0.05 0.07 0.01 0.03 0.06 0.05 0.03 0.08 0.07 0.08SEQID-02411 G1MYI4 — — 0 0.40 0.18 0.08 0.07 0.02 0.08 0.00 0.05 0.230.01 0.01 0.04 0.11 0.15 SEQID-02412 G1NCR2 — — 1 0.43 0.18 0.04 0.060.03 0.07 0.05 0.05 0.09 0.01 0.02 0.06 0.07 0.10 SEQID-02413 G1NBA6 — —1 0.48 0.20 0.04 0.07 0.04 0.06 0.01 0.04 0.09 0.03 0.03 0.06 0.07 0.09SEQID-02414 G1N314 — — 1 0.54 0.21 0.05 0.04 0.05 0.05 0.01 0.04 0.060.04 0.06 0.07 0.09 0.08 SEQID-02415 G1NBW3 — — 1 0.49 0.21 0.06 0.090.03 0.06 0.01 0.05 0.09 0.03 0.03 0.07 0.09 0.09 SEQID-02416 G1N823 — —1 0.42 0.14 0.06 0.14 0.02 0.07 0.00 0.06 0.14 0.02 0.02 0.05 0.08 0.20SEQID-02417 G3URJ0 — — 1 0.42 0.15 0.06 0.14 0.01 0.06 0.00 0.06 0.150.02 0.01 0.04 0.09 0.20 SEQID-02418 G1NAZ1 — — 1 0.47 0.21 0.03 0.070.03 0.07 0.01 0.02 0.09 0.03 0.02 0.05 0.06 0.10 SEQID-02419 G1NMV8 — —1 0.49 0.24 0.08 0.04 0.02 0.06 0.02 0.05 0.09 0.06 0.04 0.08 0.06 0.10SEQID-02420 G1NNB7 — — 1 0.46 0.20 0.03 0.04 0.02 0.18 0.01 0.02 0.120.02 0.02 0.06 0.10 0.08 SEQID-02421 G1MX98 — — 1 0.45 0.22 0.06 0.060.06 0.07 0.01 0.03 0.08 0.04 0.01 0.06 0.09 0.10 SEQID-02422 G1MWY3 — —1 0.45 0.22 0.04 0.09 0.05 0.06 0.01 0.04 0.09 0.03 0.02 0.07 0.09 0.06SEQID-02423 G1MXU8 — — 1 0.51 0.26 0.05 0.06 0.04 0.05 0.03 0.03 0.090.03 0.02 0.08 0.10 0.07 SEQID-02424 G1N5J6 — — 1 0.46 0.20 0.04 0.080.05 0.05 0.03 0.04 0.07 0.04 0.04 0.06 0.09 0.06 SEQID-02425 G1NGS2 — —1 0.46 0.17 0.04 0.08 0.04 0.07 0.01 0.03 0.07 0.04 0.06 0.05 0.07 0.08SEQID-02426 G1NK94 — — 1 0.45 0.19 0.04 0.07 0.05 0.07 0.01 0.03 0.100.03 0.02 0.06 0.06 0.10 SEQID-02427 G1MVK8 — — 1 0.44 0.23 0.05 0.090.05 0.06 0.01 0.06 0.07 0.05 0.02 0.06 0.09 0.06 SEQID-02428 G1NLT9 — —1 0.45 0.18 0.04 0.08 0.04 0.06 0.01 0.05 0.08 0.02 0.04 0.04 0.09 0.08SEQID-02429 G1N2A4 — — 1 0.43 0.21 0.08 0.07 0.04 0.06 0.02 0.05 0.080.04 0.02 0.05 0.09 0.07 SEQID-02430 G1MXB6 — — 0 0.49 0.24 0.07 0.060.05 0.04 0.02 0.03 0.07 0.05 0.02 0.07 0.10 0.09 SEQID-02431 G1NAR9 — —1 0.39 0.17 0.03 0.07 0.03 0.06 0.01 0.05 0.15 0.04 0.02 0.05 0.09 0.07SEQID-02432 G1MVB6 — — 1 0.49 0.24 0.05 0.07 0.04 0.04 0.02 0.04 0.090.03 0.02 0.07 0.09 0.06 SEQID-02433 G1MT65 — — 1 0.48 0.21 0.04 0.070.03 0.07 0.01 0.04 0.07 0.03 0.02 0.07 0.07 0.11 SEQID-02434 G1N3V6 — —1 0.49 0.21 0.05 0.06 0.04 0.05 0.01 0.03 0.08 0.05 0.02 0.08 0.06 0.11SEQID-02435 G1NMW0 — — 1 0.43 0.22 0.06 0.07 0.05 0.09 0.01 0.03 0.090.04 0.02 0.06 0.09 0.07 SEQID-02436 G1NLY5 — — 1 0.48 0.23 0.05 0.080.04 0.07 0.01 0.03 0.09 0.03 0.04 0.07 0.08 0.08 SEQID-02437 G1N9H8 — —0 0.58 0.25 0.08 0.03 0.03 0.05 0.01 0.02 0.05 0.03 0.09 0.06 0.11 0.10SEQID-02438 G1N8B8 — — 1 0.45 0.17 0.06 0.11 0.03 0.06 0.01 0.05 0.130.02 0.03 0.02 0.12 0.16 SEQID-02439 G1MWQ38 — — 1 0.42 0.11 0.03 0.060.04 0.04 0.11 0.03 0.07 0.03 0.04 0.03 0.03 0.12 SEQID-02440 G1NR17 — —1 0.46 0.20 0.05 0.07 0.05 0.08 0.01 0.05 0.09 0.04 0.01 0.07 0.07 0.10SEQID-02441 G1NB19 — — 1 0.44 0.17 0.03 0.09 0.02 0.04 0.01 0.04 0.110.02 0.03 0.05 0.06 0.09 SEQID-02442 PB2013 — — 1 0.50 0.19 0.05 0.030.06 0.06 0.01 0.02 0.05 0.06 0.01 0.05 0.09 0.11 SEQID-02443 G1N478 — —1 0.44 0.15 0.03 0.07 0.04 0.04 0.00 0.03 0.08 0.06 0.05 0.04 0.07 0.10SEQID-02444 G1MSQ3 — — 1 0.46 0.19 0.06 0.09 0.04 0.05 0.01 0.04 0.060.04 0.03 0.06 0.08 0.08 SEQID-02445 G1N0V4 — — 1 0.43 0.17 0.07 0.060.03 0.04 0.01 0.04 0.11 0.03 0.03 0.05 0.06 0.10 SEQID-02446 G1MSW3 — —1 0.46 0.21 0.05 0.06 0.05 0.07 0.01 0.05 0.09 0.04 0.01 0.07 0.07 0.10SEQID-02447 H9H1S2 — — 0 0.51 0.22 0.05 0.03 0.05 0.03 0.04 0.06 0.080.05 0.02 0.06 0.09 0.10 SEQID-02448 Q6W5H1 — — 0 0.46 0.17 0.08 0.020.05 0.06 0.00 0.04 0.13 0.03 0.01 0.05 0.07 0.13 SEQID-02449 G1MRV9 — —0 0.45 0.23 0.07 0.03 0.02 0.05 0.01 0.07 0.06 0.04 0.02 0.07 0.10 0.07SEQID-02450 G1N0M3 — — 1 0.42 0.21 0.03 0.12 0.05 0.05 0.02 0.04 0.090.05 0.03 0.05 0.10 0.06 SEQID-02451 H9H062 — — 0 0.47 0.25 0.07 0.070.02 0.06 0.00 0.05 0.10 0.05 0.02 0.08 0.09 0.06 SEQID-02452 G3URQ7 — —1 0.45 0.19 0.07 0.03 0.01 0.03 0.00 0.06 0.12 0.02 0.03 0.06 0.04 0.09SEQID-02453 G1NPZ8 — — 1 0.56 0.25 0.07 0.05 0.04 0.05 0.01 0.04 0.040.03 0.07 0.05 0.12 0.09 SEQID-02454 G1N3B7 — — 1 0.50 0.22 0.06 0.030.03 0.05 0.01 0.05 0.03 0.05 0.01 0.08 0.07 0.10 SEQID-02455 G1N8F8 — —1 0.44 0.17 0.05 0.06 0.05 0.05 0.02 0.05 0.10 0.04 0.03 0.03 0.08 0.04SEQID-02456 G1MV26 — — 1 0.47 0.23 0.05 0.09 0.04 0.05 0.02 0.04 0.070.05 0.03 0.06 0.10 0.06 SEQID-02457 G1NFA2 — — 1 0.49 0.22 0.05 0.070.03 0.07 0.02 0.04 0.08 0.04 0.02 0.06 0.09 0.09 SEQID-02458 G1N0S1 — —1 0.47 0.23 0.03 0.07 0.04 0.06 0.02 0.06 0.07 0.03 0.03 0.07 0.11 0.07SEQID-02459 G1NHY3 — — 1 0.48 0.22 0.03 0.06 0.04 0.05 0.02 0.04 0.100.03 0.03 0.06 0.11 0.08 SEQID-02460 G1MUC1 — — 1 0.47 0.20 0.04 0.060.03 0.05 0.02 0.04 0.11 0.03 0.02 0.05 0.08 0.11 SEQID-02461 G1NC68 — —0 0.43 0.26 0.05 0.10 0.03 0.07 0.01 0.04 0.07 0.05 0.01 0.08 0.09 0.06SEQID-02462 G1NL16 — — 1 0.49 0.21 0.03 0.08 0.05 0.09 0.01 0.04 0.070.05 0.04 0.04 0.11 0.08 SEQID-02463 G1NFQ5 — — 1 0.44 0.20 0.05 0.060.04 0.06 0.02 0.04 0.09 0.04 0.04 0.06 0.07 0.05 SEQID-02464 G1N3X9 — —1 0.45 0.21 0.06 0.09 0.03 0.09 0.01 0.04 0.09 0.03 0.02 0.06 0.11 0.09SEQID-02465 G1MUF1 — — 1 0.43 0.21 0.06 0.10 0.04 0.07 0.01 0.04 0.090.04 0.02 0.07 0.09 0.06 SEQID-02466 G1MVN4 — — 1 0.46 0.20 0.05 0.060.04 0.06 0.04 0.05 0.07 0.04 0.02 0.04 0.10 0.09 SEQID-02467 G1NBN7 — —1 0.47 0.23 0.04 0.07 0.03 0.05 0.02 0.06 0.08 0.04 0.04 0.05 0.12 0.06SEQID-02468 G1N481 — — 0 0.46 0.19 0.06 0.03 0.01 0.09 0.01 0.02 0.090.05 0.00 0.04 0.10 0.15 SEQID-02469 G1MX59 — — 1 0.45 0.17 0.04 0.080.01 0.04 0.00 0.03 0.10 0.03 0.03 0.05 0.07 0.07 SEQID-02470 G1NLB3 — —1 0.46 0.22 0.03 0.08 0.05 0.05 0.01 0.05 0.10 0.03 0.03 0.05 0.12 0.08SEQID-02471 G1N1G2 — — 1 0.44 0.21 0.03 0.07 0.04 0.10 0.01 0.06 0.060.03 0.02 0.04 0.11 0.10 SEQID-02472 G1N071 — — 1 0.51 0.26 0.06 0.050.04 0.07 0.01 0.03 0.07 0.03 0.02 0.07 0.10 0.11 SEQID-02473 G1NB81 — —1 0.48 0.19 0.04 0.08 0.05 0.05 0.01 0.05 0.05 0.04 0.02 0.04 0.09 0.06SEQID-02474 G1MZD9 — — 1 0.45 0.21 0.05 0.08 0.04 0.08 0.01 0.04 0.090.03 0.01 0.07 0.10 0.11 SEQID-02475 G1NL53 — — 1 0.50 0.23 0.04 0.060.04 0.06 0.01 0.05 0.08 0.06 0.03 0.07 0.08 0.09 SEQID-02476 G1NAW6 — —1 0.50 0.25 0.03 0.09 0.04 0.06 0.01 0.05 0.09 0.03 0.01 0.08 0.10 0.06SEQID-02477 G1NB27 — — 1 0.40 0.16 0.05 0.07 0.06 0.05 0.01 0.09 0.070.03 0.03 0.04 0.08 0.08 SEQID-02478 G1NCE0 — — 1 0.48 0.23 0.06 0.070.04 0.04 0.01 0.05 0.07 0.04 0.02 0.06 0.11 0.06 SEQID-02479 G1NGS1 — —1 0.45 0.18 0.05 0.04 0.04 0.06 0.02 0.05 0.10 0.03 0.02 0.04 0.09 0.10SEQID-02480 G1NKX1 — — 1 0.47 0.20 0.03 0.06 0.04 0.07 0.01 0.04 0.150.02 0.02 0.06 0.09 0.12 SEQID-02481 G1NRH0 — — 0 0.51 0.16 0.06 0.0380.02 0.02 0.00 0.03 0.06 0.03 0.04 0.06 0.05 0.18 SEQID-02482 G1NQ36 — —0 0.48 0.20 0.04 0.06 0.04 0.06 0.02 0.03 0.13 0.04 0.03 0.08 0.06 0.09SEQID-02483 G1MK52 — — 1 0.40 0.20 0.05 0.06 0.06 0.06 0.01 0.05 0.130.02 0.02 0.04 0.10 0.08 SEQID-02484 G1NCP5 — — 1 0.43 0.15 0.04 0.060.05 0.03 0.02 0.05 0.16 0.02 0.01 0.05 0.06 0.10 SEQID-02485 G1MZ49 — —0 0.48 0.25 0.04 0.07 0.07 0.06 0.02 0.03 0.07 0.02 0.02 0.07 0.14 0.07SEQID-02486 G1NGA7 — — 1 0.50 0.21 0.06 0.06 0.02 0.02 0.02 0.04 0.060.04 0.01 0.05 0.09 0.08 SEQID-02487 G1NLA9 — — 1 0.48 0.21 0.06 0.040.05 0.05 0.02 0.05 0.08 0.03 0.03 0.06 0.09 0.10 SEQID-02488 G1NAL4 — —1 0.44 0.18 0.06 0.06 0.02 0.04 0.04 0.05 0.11 0.04 0.03 0.05 0.07 0.08SEQID-02489 G1NCM2 — — 1 0.50 0.21 0.06 0.06 0.04 0.05 0.01 0.05 0.110.02 0.02 0.04 0.12 0.11 SEQID-02490 G1NP43 — — 1 0.39 0.16 0.04 0.120.04 0.07 0.01 0.04 0.07 0.06 0.02 0.05 0.08 0.05 SEQID-02491 G1NMS8 — —1 0.48 0.23 0.07 0.06 0.03 0.05 0.01 0.06 0.06 0.05 0.02 0.06 0.09 0.10SEQID-02492 G1MSI1 — — 1 0.38 0.18 0.04 0.09 0.03 0.07 0.02 0.05 0.080.08 0.01 0.06 0.07 0.07 SEQID-02493 G1NP96 — — 1 0.46 0.22 0.04 0.070.04 0.07 0.02 0.06 0.08 0.02 0.03 0.06 0.11 0.07 SEQID-02494 P07728 — —1 0.35 0.19 0.04 0.11 0.07 0.03 0.02 0.12 0.06 0.04 0.02 0.05 0.08 0.03SEQID-02495 P07730 — — 1 0.37 0.19 0.04 0.11 0.07 0.03 0.02 0.12 0.060.04 0.02 0.05 0.08 0.03 SEQID-02496 P14323 — — 1 0.38 0.19 0.04 0.090.07 0.02 0.01 0.12 0.06 0.03 0.03 0.05 0.07 0.04 SEQID-02497 Q02897 — —1 0.38 0.18 0.04 0.09 0.07 0.02 0.01 0.12 0.06 0.03 0.02 0.05 0.07 0.04SEQID-02498 P14614 — — 1 0.38 0.19 0.05 0.10 0.08 0.02 0.01 0.12 0.070.04 0.03 0.05 0.09 0.03 SEQID-02499 Q09151 — — 1 0.39 0.20 0.04 0.100.06 0.05 0.02 0.12 0.05 0.04 0.03 0.05 0.08 0.03 SEQID-02500 Q01401 — —1 0.46 0.17 0.04 0.08 0.05 0.07 0.01 0.02 0.07 0.04 0.05 0.04 0.07 0.07SEQID-02501 Q6K508 — — 1 0.40 0.21 0.05 0.11 0.06 0.04 0.01 0.11 0.060.04 0.03 0.06 0.08 0.04 SEQID-02502 Q6K7K6 — — 1 0.42 0.20 0.05 0.100.05 0.04 0.01 0.11 0.06 0.03 0.04 0.05 0.09 0.03 SEQID-02503 Q0E2G5 — —1 0.41 0.20 0.04 0.10 0.09 0.02 0.01 0.10 0.06 0.04 0.03 0.07 0.08 0.05SEQID-02504 Q6H6P8 — — 1 0.43 0.17 0.05 0.08 0.04 0.07 0.01 0.02 0.070.05 0.04 0.04 0.07 0.05 SEQID-02505 Q7X834 — — 1 0.44 0.21 0.05 0.080.05 0.08 0.01 0.04 0.05 0.04 0.04 0.05 0.08 0.04 SEQID-02506 Q0DEV5 — —1 0.45 0.21 0.07 0.08 0.04 0.06 0.02 0.03 0.07 0.05 0.02 0.05 0.08 0.08SEQID-02507 Q6AVA8 — — 1 0.45 0.21 0.07 0.09 0.03 0.05 0.02 0.04 0.090.05 0.03 0.04 0.09 0.06 SEQID-02508 Q43009 — — 1 0.49 0.22 0.04 0.080.04 0.04 0.01 0.04 0.09 0.03 0.05 0.06 0.11 0.06 SEQID-02509 Q5VNT5 — —1 0.46 0.21 0.04 0.07 0.04 0.07 0.02 0.04 0.07 0.04 0.03 0.09 0.07 0.06SEQID-02510 P15280 — — 1 0.43 0.22 0.06 0.08 0.05 0.07 0.01 0.03 0.060.04 0.02 0.08 0.08 0.06 SEQID-02511 P30298 — — 1 0.48 0.22 0.04 0.070.04 0.06 0.01 0.04 0.08 0.03 0.04 0.06 0.11 0.06 SEQID-02512 Q10LP5 — —1 0.47 0.23 0.04 0.08 0.04 0.05 0.01 0.04 0.08 0.03 0.04 0.07 0.10 0.06SEQID-02513 Q0DI45 — — 1 0.38 0.25 0.08 0.06 0.04 0.03 0.01 0.20 0.010.02 0.01 0.06 0.13 0.01 SEQID-02514 Q9AUv8 — — 1 0.47 0.21 0.05 0.070.05 0.06 0.01 0.03 0.10 0.04 0.03 0.06 0.08 0.08 SEQID-02515 Q6Z7B0 — —1 0.46 0.22 0.05 0.07 0.05 0.07 0.01 0.04 0.12 0.05 0.01 0.07 0.08 0.11SEQID-02516 P37833 — — 1 0.46 0.22 0.06 0.08 0.03 0.05 0.01 0.05 0.050.04 0.03 0.06 0.10 0.05 SEQID-02517 Q6K5G8 — — 1 0.52 0.22 0.06 0.050.04 0.07 0.01 0.02 0.07 0.04 0.03 0.06 0.06 0.10 SEQID-02518 Q6Z7B2 — —1 0.44 0.22 0.09 0.11 0.02 0.02 0.02 0.01 0.09 0.05 0.02 0.04 0.09 0.06SEQID-02519 Q75GX9 — — 1 0.33 0.16 0.06 0.18 0.03 0.05 0.01 0.06 0.130.04 0.03 0.04 0.07 0.04 SEQID-02520 Q2QV45 — — 1 0.46 0.22 0.07 0.060.04 0.09 0.01 0.05 0.08 0.05 0.01 0.05 0.08 0.09 SEQID-02521 Q84Q83 — —1 0.44 0.19 0.04 0.08 0.05 0.05 0.01 0.05 0.07 0.07 0.03 0.04 0.08 0.06SEQID-02522 O64937 — — 1 0.52 0.21 0.04 0.06 0.04 0.06 0.01 0.02 0.080.04 0.03 0.07 0.06 0.13 SEQID-02523 Q6T725 — — 1 0.40 0.20 0.03 0.090.07 0.03 0.01 0.11 0.07 0.03 0.03 0.06 0.08 0.03 SEQID-02524 P29835 — —0 0.26 0.12 0.06 0.16 0.00 0.03 0.04 0.13 0.10 0.04 0.00 0.02 0.06 0.01SEQID-02525 Q5N725 — — 1 0.46 0.22 0.07 0.05 0.04 0.04 0.02 0.04 0.100.05 0.02 0.05 0.10 0.10 SEQID-02526 Q6ZBH2 — — 1 0.47 0.24 0.08 0.100.02 0.05 0.03 0.01 0.10 0.06 0.04 0.05 0.07 0.05 SEQID-02527 Q338N8 — —1 0.42 0.23 0.07 0.06 0.05 0.05 0.02 0.06 0.07 0.04 0.02 0.08 0.10 0.07SEQID-02528 Q53LQ0 — — 1 0.48 0.20 0.07 0.03 0.03 0.08 0.01 0.03 0.110.03 0.02 0.05 0.08 0.12 SEQID-02529 Q01B82 — — 1 0.39 0.20 0.07 0.110.03 0.06 0.06 0.04 0.04 0.06 0.05 0.03 0.08 0.02 SEQID-02530 Q7FAH2 — —1 0.51 0.22 0.06 0.05 0.04 0.08 0.01 0.02 0.07 0.04 0.02 0.06 0.06 0.10SEQID-02531 Q852L2 — — 1 0.38 0.17 0.05 0.14 0.02 0.03 0.01 0.03 0.130.05 0.04 0.03 0.07 0.04 SEQID-02532 Q6H4L2 — — 1 0.48 0.21 0.05 0.070.03 0.06 0.02 0.04 0.09 0.04 0.02 0.05 0.08 0.08 SEQID-02533 P35683 — —1 0.46 0.23 0.093 0.10 0.03 0.08 0.01 0.07 0.08 0.04 0.02 0.06 0.09 0.05SEQID-02534 Q6Z2Z4 — — 1 0.46 0.23 0.03 0.10 0.03 0.08 0.01 0.07 0.070.04 0.02 0.06 0.10 0.05 SEQID-02535 Q6H6C7 — — 1 0.53 0.26 0.09 0.030.02 0.07 0.00 0.01 0.08 0.05 0.01 0.05 0.12 0.12 SEQID-02536 Q7XTK1 — —1 0.48 0.22 0.05 0.07 0.03 0.06 0.02 0.04 0.09 0.04 0.02 0.05 0.08 0.08SEQID-02537 P20698 — — 1 0.40 0.20 0.07 0.04 0.02 0.01 0.05 0.22 0.010.01 0.02 0.06 0.08 0.01 SEQID-02538 Q2QXY9 — — 1 0.43 0.21 0.08 0.090.03 0.06 0.01 0.03 0.08 0.04 0.04 0.07 0.07 0.05 SEQID-02539 Q93X08 — —1 0.51 0.26 0.04 0.04 0.07 0.06 0.01 0.03 0.08 0.04 0.02 0.07 0.11 0.10SEQID-02540 Q8H4L8 — — 1 0.38 0.21 0.08 0.12 0.03 0.05 0.06 0.05 0.040.05 0.03 0.05 0.07 0.02 SEQID-02541 Q655T1 — — 1 0.53 0.26 0.07 0.030.02 0.07 0.00 0.01 0.07 0.05 0.01 0.06 0.12 0.12 SEQID-02542 Q0J8A4 — —1 0.52 0.23 0.06 0.05 0.04 0.08 0.01 0.01 0.05 0.04 0.02 0.08 0.06 0.10SEQID-02543 Q69T99 — — 1 0.43 0.22 0.07 0.09 0.05 0.06 0.01 0.03 0.070.04 0.02 0.09 0.07 0.06 SEQID-02544 Q653V7 — — 1 0.45 0.21 0.06 0.100.04 0.06 0.00 0.02 0.09 0.06 0.03 0.03 0.10 0.03 SEQID-02545 Q01881 — —1 0.36 0.20 0.09 0.13 0.02 0.05 0.06 0.04 0.04 0.05 0.03 0.02 0.09 0.01SEQID-02546 Q8H4M4 — — 1 0.42 0.20 0.07 0.10 0.01 0.05 0.06 0.05 0.020.05 0.02 0.03 0.08 0.04 SEQID-02547 Q6ZIX4 — — 1 0.41 0.26 0.06 0.040.03 0.01 0.03 0.22 0.01 0.01 0.02 0.07 0.11 0.01 SEQID-02548 Q10P83 — —1 0.48 0.25 0.04 0.09 0.05 0.06 0.01 0.04 0.06 0.04 0.02 0.07 0.10 0.07SEQID-02549 Q10DV7 — — 1 0.47 0.21 0.05 0.07 0.02 0.06 0.01 0.03 0.080.04 0.03 0.08 0.07 0.06 SEQID-02550 Q7X8H9 — — 1 0.37 0.20 0.10 0.100.02 0.06 0.06 0.04 0.04 0.07 0.02 0.03 0.08 0.02 SEQID-02551 Q0J4C6 — —1 0.45 0.17 0.04 0.06 0.05 0.06 0.02 0.02 0.07 0.05 0.04 0.04 0.08 0.04SEQID-02552 A1YQF0 — — 1 0.37 0.25 0.08 0.06 0.05 0.03 0.00 0.19 0.010.02 0.02 0.06 0.15 0.01 SEQID-02553 Q5Z9M9 — — 1 0.37 0.16 0.06 0.060.02 0.01 0.08 0.20 0.02 0.02 0.02 0.03 0.07 0.02 SEQID-02554 P17048 — —1 0.41 0.24 0.06 0.04 0.03 0.01 0.03 0.22 0.01 0.01 0.02 0.07 0.10 0.01SEQID-02555 Q5Z627 — — 1 0.50 0.19 0.04 0.04 0.05 0.05 0.01 0.02 0.100.03 0.01 0.04 0.09 0.11 SEQID-02556 Q65XV6 — — 1 0.50 0.21 0.07 0.070.04 0.07 0.02 0.00 0.05 0.07 0.04 0.08 0.06 0.09 SEQID-02557 Q7X7E6 — —1 0.35 0.19 0.11 0.11 0.02 0.06 0.06 0.03 0.05 0.06 0.02 0.03 0.08 0.02SEQID-02558 Q8GVK7 — — 0 0.40 0.28 0.07 0.06 0.05 0.03 0.01 0.19 0.010.02 0.02 0.07 0.15 0.01 SEQID-02559 Q0DJ38 — — 1 0.39 0.25 0.06 0.050.04 0.03 0.01 0.18 0.01 0.02 0.01 0.06 0.16 0.01 SEQID-02560 Q75HX0 — —1 0.46 0.21 0.04 0.07 0.02 0.06 0.01 0.03 0.08 0.04 0.03 0.07 0.07 0.06SEQID-02561 Q0JKM8 — — 1 0.46 0.22 0.07 0.06 0.04 0.05 0.02 0.06 0.050.06 0.03 0.06 0.098 0.06 SEQID-02562 Q7XDC8 — — 1 0.47 0.24 0.07 0.050.05 0.05 0.02 0.04 0.07 0.04 0.02 0.06 0.09 0.07 SEQID-02563 Q5W6C5 — —1 0.42 0.19 0.06 0.08 0.04 0.06 0.01 0.04 0.04 0.04 0.03 0.03 0.10 0.04SEQID-02564 Q10M12 — — 1 0.45 0.15 0.04 0.07 0.06 0.07 0.02 0.04 0.070.06 0.07 0.04 0.05 0.06 SEQID-02565 Q6YW46 — — 1 0.49 0.18 0.05 0.040.05 0.05 0.01 0.02 0.10 0.03 0.01 0.04 0.08 0.12 SEQID-02566 Q9AUQ4 — —1 0.48 0.21 0.06 0.05 0.04 0.08 0.01 0.03 0.06 0.05 0.02 0.05 0.07 0.08SEQID-02567 Q01883 — — 1 0.36 0.19 0.08 0.12 0.02 0.05 0.06 0.05 0.040.05 0.04 0.02 0.09 0.01 SEQID-02568 Q0JDG9 — — 1 0.41 0.24 0.07 0.080.04 0.05 0.01 0.04 0.07 0.07 0.01 0.05 0.12 0.03 SEQID-02569 P49027 — —1 0.47 0.23 0.04 0.06 0.05 0.07 0.02 0.03 0.04 0.06 0.03 0.05 0.10 0.05SEQID-02570 Q0ISV7 — — 1 0.486 0.22 0.05 0.07 0.03 0.06 0.02 0.03 0.080.04 0.02 0.06 0.09 0.08 SEQID-02571 Q0DUA3 — — 1 0.38 0.15 0.04 0.130.03 0.05 0.01 0.04 0.16 0.05 0.04 0.04 0.05 0.07 SEQID-02572 Q53NM9 — —1 0.45 0.21 0.06 0.07 0.05 0.08 0.01 0.05 0.09 0.04 0.01 0.08 0.07 0.09SEQID-02573 Q07078 — — 1 0.49 0.20 0.03 0.05 0.04 0.07 0.01 0.03 0.140.02 0.02 0.06 0.09 0.13 SEQID-02574 Q42465 — — 1 0.41 0.26 0.08 0.050.05 0.03 0.01 0.18 0.01 0.02 0.02 0.07 0.14 0.01 SEQID-02575 P48494 — —1 0.49 0.25 0.07 0.05 0.04 0.05 0.02 0.05 0.09 0.05 0.01 0.06 0.07 0.08SEQID-02576 Q2QNF3 — — 1 0.43 0.17 0.07 0.15 0.04 0.03 0.01 0.03 0.030.07 0.07 0.05 0.04 0.08 SEQID-02577 Q948T6 — — 1 0.47 0.21 0.05 0.050.02 0.07 0.02 0.02 0.09 0.04 0.01 0.05 0.10 0.11 SEQID-02578 Q9ZRI7 — —1 0.49 0.17 0.06 0.04 0.05 0.05 0.01 0.02 0.10 0.03 0.01 0.04 0.08 0.12SEQID-02579 Q42971 — — 1 0.45 0.22 0.07 0.04 0.06 0.06 0.01 0.05 0.080.05 0.01 0.06 0.08 0.10 SEQID-02580 Q0DEC8 — — 1 0.44 0.20 0.05 0.080.03 0.06 0.01 0.04 0.07 0.05 0.03 0.04 0.09 0.05 SEQID-02581 Q0DDE3 — —1 0.39 0.19 0.07 0.10 0.03 0.09 0.01 0.03 0.07 0.05 0.03 0.03 0.07 0.05SEQID-02582 Q07661 — — 1 0.47 0.20 0.05 0.09 0.03 0.05 0.00 0.03 0.0890.05 0.02 0.09 0.05 0.06 SEQID-02583 Q0D868 — — 1 0.46 0.19 0.09 0.130.04 0.03 0.00 0.02 0.06 0.04 0.03 0.04 0.08 0.11 SEQID-02584 Q7XC37 — —1 0.51 0.23 0.05 0.07 0.03 0.03 0.00 0.03 0.10 0.05 0.02 0.03 0.06 0.08SEQID-02585 Q6ZKC0 — — 1 0.43 0.20 0.07 0.07 0.03 0.06 0.01 0.03 0.150.03 0.02 0.05 0.11 0.09 SEQID-02586 Q7XTE8 — — 1 0.41 0.20 0.06 0.080.03 0.06 0.01 0.03 0.15 0.02 0.01 0.06 0.10 0.08 SEQID-02587 Q65XA1 — —1 0.49 0.23 0.06 0.05 0.04 0.05 0.01 0.03 0.06 0.06 0.02 0.06 0.10 0.07SEQID-02588 Q0DJB9 — — 1 0.47 0.23 0.06 0.04 0.03 0.10 0.00 0.05 0.090.05 0.01 0.05 0.10 0.10 SEQID-02589 Q0DBN4 — — 1 0.45 0.18 0.07 0.090.03 0.05 0.02 0.04 0.06 0.04 0.04 0.06 0.08 0.06 SEQID-02590 Q2QVC1 — —1 0.44 0.22 0.07 0.07 0.03 0.05 0.01 0.02 0.09 0.05 0.03 0.06 0.09 0.08SEQID-02591 P0C522 — — 0 0.42 0.25 0.07 0.09 0.04 0.05 0.01 0.06 0.080.04 0.01 0.07 0.10 0.06 SEQID-02592 Q01859 — — 0 0.44 0.24 0.07 0.090.03 0.05 0.00 0.05 0.08 0.05 0.03 0.06 0.10 0.05 SEQID-02593 Q0J1E1 — —1 0.47 0.23 0.07 0.07 0.03 0.06 0.02 0.03 0.05 0.05 0.04 0.07 0.09 0.07SEQID-02594 Q2QLY4 — — 1 0.48 0.22 0.07 0.06 0.04 0.06 0.01 0.03 0.080.03 0.02 0.06 0.09 0.08 SEQID-02595 Q6YZX6 — — 1 0.48 0.22 0.05 0.050.05 0.06 0.01 0.03 0.07 0.05 0.03 0.05 0.09 0.07 SEQID-02596 Q0DKN6 — —1 0.37 0.20 0.07 0.06 0.04 0.08 0.00 0.04 0.14 0.04 0.01 0.04 0.09 0.07SEQID-02597 P0C030 — — 0 0.50 0.26 0.03 0.07 0.02 0.08 0.00 0.07 0.100.04 0.02 0.11 0.11 0.11 SEQID-02598 P35681 — — 1 0.49 0.21 0.03 0.020.02 0.12 0.01 0.05 0.09 0.05 0.01 0.04 0.10 0.11 SEQID-02599 Q8H920 — —1 0.44 0.21 0.17 0.09 0.02 0.02 0.02 0.03 0.03 0.07 0.04 0.01 0.16 0.01SEQID-02600 P29421 — — 1 0.39 0.21 0.06 0.12 0.01 0.05 0.02 0.02 0.060.05 0.03 0.03 0.10 0.03 SEQID-02601 Q6YTY2 — — 1 0.47 0.23 0.05 0.110.03 0.04 0.01 0.03 0.08 0.04 0.02 0.06 0.09 0.09 SEQID-02602 Q10QU9 — —1 0.41 0.18 0.11 0.07 0.03 0.07 0.01 0.03 0.06 0.04 0.02 0.06 0.06 0.03SEQID-02603 Q0DS36 — — 1 0.45 0.18 0.06 0.07 0.03 0.04 0.01 0.03 0.100.06 0.02 0.03 0.07 0.09 SEQID-02604 Q9SXP2 — — 1 0.47 0.22 0.07 0.070.04 0.06 0.01 0.03 0.07 0.05 0.04 0.06 0.09 0.08 SEQID-02605 Q5W6H1 — —1 0.50 0.23 0.06 0.04 0.04 0.07 0.02 0.03 0.10 0.03 0.03 0.06 0.08 0.13SEQID-02606 P35684 — — 1 0.54 0.18 0.03 0.10 0.01 0.04 0.02 0.04 0.060.04 0.05 0.05 0.06 0.15 SEQID-02607 Q6ZK46 — — 1 0.33 0.18 0.07 0.180.04 0.06 0.01 0.05 0.09 0.05 0.02 0.04 0.07 0.02 SEQID-02608 Q6ZHC3 — —1 0.42 0.20 0.07 0.08 0.03 0.04 0.02 0.06 0.10 0.03 0.02 0.07 0.08 0.07SEQID-02609 Q6SXK0 — — 1 0.45 0.21 0.08 0.07 0.03 0.05 0.01 0.03 0.080.04 0.03 0.06 0.08 0.06 SEQID-02610 Q67IX6 — — 1 0.47 0.21 0.07 0.040.04 0.10 0.01 0.03 0.09 0.02 0.03 0.05 0.10 0.09 SEQID-02611 Q6H547 — —1 0.41 0.20 0.06 0.10 0.03 0.06 0.01 0.05 0.09 0.04 0.01 0.05 0.08 0.07SEQID-02612 P0C5C9 — — 1 0.48 0.20 0.05 0.06 0.03 0.10 0.01 0.02 0.050.05 0.04 0.05 0.07 0.10 SEQID-02613 Q0DKF0 — — 1 0.44 0.17 0.06 0.150.03 0.04 0.C3 0.03 0.05 0.04 0.04 0.04 0.06 0.11 SEQID-02614 P35685 — —1 0.54 0.22 0.06 0.10 0.03 0.03 0.01 0.04 0.07 0.03 0.02 0.04 0.10 0.18SEQID-02615 Q8L4L4 — — 0 0.42 0.16 0.06 0.11 0.03 0.08 0.00 0.04 0.080.04 0.03 0.04 0.08 0.10 SEQID-02616 Q6Z4N6 — — 1 0.49 0.17 0.04 0.060.06 0.07 0.02 0.03 0.06 0.04 0.06 0.04 0.06 0.08 SEQID-02617 Q7XHN4 — —1 0.43 0.20 0.06 0.07 0.05 0.06 0.02 0.05 0.03 0.05 0.02 0.05 0.07 0.05SEQID-02618 Q6F2Y7 — — 1 0.43 0.25 0.07 0.12 0.02 0.07 0.00 0.05 0.110.04 0.03 0.05 0.12 0.07 SEQID-02619 Q8GVI3 — — 1 0.35 0.20 0.11 0.120.01 0.04 0.07 0.02 0.07 0.04 0.02 0.02 0.15 0.02 SEQID-02620 P27777 — —1 0.47 0.20 0.04 0.09 0.05 0.07 0.00 0.02 0.11 0.02 0.02 0.03 0.05 0.11SEQID-02621 Q53NL5 — — 1 0.41 0.18 0.09 0.09 0.03 0.08 0.01 0.03 0.040.06 0.04 0.04 0.10 0.04 SEQID-02622 P41095 — — 0 0.49 0.25 0.06 0.040.04 0.06 0.01 0.02 0.09 0.04 0.01 0.06 0.10 0.11 SEQID-02623 Q8H916 — —1 0.44 0.19 0.05 0.09 0.05 0.07 0.00 0.03 0.07 0.03 0.03 0.06 0.09 0.06SEQID-02624 Q4W8D0 — — 1 0.42 0.18 0.05 0.08 0.05 0.07 0.01 0.03 0.060.06 0.04 0.07 0.05 0.06 SEQID-02625 Q9LD54 — — 1 0.47 0.23 0.07 0.080.03 0.03 0.01 0.04 0.06 0.06 0.02 0.04 0.12 0.07 SEQID-02626 P46265 — —1 0.43 0.17 0.04 0.07 0.05 0.07 0.02 0.05 0.09 0.04 0.03 0.04 0.08 0.04SEQID-02627 Q53M52 — — 1 0.43 0.21 0.04 0.07 0.04 0.07 0.02 0.04 0.090.04 0.03 0.05 0.09 0.05 SEQID-02628 Q10R45 — — 1 0.45 0.22 0.06 0.070.04 0.04 0.01 0.04 0.07 0.06 0.03 0.05 0.10 0.07 SEQID-02629 Q69P84 — —1 0.46 0.24 0.06 0.07 0.05 0.03 0.02 0.05 0.07 0.06 0.02 0.09 0.09 0.04SEQID-02630 Q33AE4 — — 1 0.45 0.21 0.06 0.08 0.04 0.08 0.00 0.03 0.050.05 0.02 0.06 0.09 0.07 SEQID-02631 Q0JCZ5 — — 1 0.47 0.19 0.04 0.100.03 0.05 0.01 0.03 0.11 0.03 0.01 0.05 0.08 0.10 SEQID-02632 Q9FWV2 — —1 0.44 0.24 0.08 0.07 0.03 0.06 0.01 0.05 0.10 0.03 0.01 0.06 0.12 0.09SEQID-02633 P31674 — — 0 0.48 0.20 0.05 0.13 0.02 0.05 0.00 0.03 0.070.04 0.03 0.06 0.07 0.12 SEQID-02634 Q84Q77 — — 1 0.44 0.16 0.04 0.090.03 0.07 0.00 0.04 0.11 0.04 0.02 0.05 0.05 0.10 SEQID-02635 Q0JBY8 — —1 0.53 0.17 0.04 0.11 0.04 0.01 0.03 0.03 0.04 0.05 0.04 0.08 0.04 0.16SEQID-02636 Q8H590 — — 1 0.51 0.20 0.03 0.16 0.05 0.07 0.01 0.04 0.040.04 0.03 0.04 0.10 0.12 SEQID-02637 Q6K1W6 — — 1 0.41 0.16 0.07 0.140.05 0.03 0.01 0.05 0.07 0.03 0.04 0.05 0.06 0.11 SEQID-02638 P49199 — —1 0.43 0.16 0.06 0.14 0.04 0.04 0.01 0.06 0.07 0.05 0.02 0.03 0.07 0.14SEQID-02639 Q40680 — — 1 0.44 0.21 0.07 0.03 0.03 0.11 0.00 0.02 0.050.03 0.01 0.04 0.09 0.09 SEQID-02640 Q7GD79 — — 1 0.48 0.20 0.05 0.060.05 0.07 0.02 0.05 0.07 0.03 0.04 0.05 0.08 0.09 SEQID-02641 Q0JDZ7 — —1 0.43 0.16 0.06 0.14 0.04 0.04 0.01 0.06 0.07 0.05 0.02 0.03 0.07 0.14SEQID-02642 Q8LH97 — — 0 0.45 0.17 0.05 0.16 0.03 0.06 0.01 0.05 0.080.04 0.00 0.04 0.08 0.16 SEQID-02643 Q6K8B8 — — 1 0.51 0.20 0.04 0.100.03 0.06 0.01 0.05 0.07 0.03 0.01 0.06 0.07 0.14 SEQID-02644 Q84M35 — —1 0.49 0.20 0.04 0.13 0.02 0.03 0.01 0.03 0.07 0.07 0.02 0.04 0.06 0.10SEQID-02645 Q75KH3 — — 1 0.40 0.19 0.08 0.09 0.04 0.06 0.01 0.05 0.070.05 0.01 0.07 0.06 0.06 SEQID-02646 Q6F361 — — 0 0.47 0.25 0.09 0.050.05 0.04 0.01 0.03 0.09 0.05 0.02 0.05 0.11 0.09 SEQID-02647 Q6Z9P5 — —1 0.53 0.124 0.05 0.05 0.03 0.07 0.01 0.02 0.07 0.04 0.04 0.09 0.09 0.06SEQID-02648 Q75H81 — — 1 0.51 0.123 0.09 0.03 0.02 0.05 0.00 0.05 0.070.04 0.04 0.03 0.13 0.08 SEQID-02649 Q6Z1J6 — — 1 0.50 0.21 0.05 0.060.03 0.07 0.02 0.03 0.09 0.03 0.03 0.08 0.07 0.11 SEQID-02650 Q62744 — —1 0.45 0.20 0.06 0.09 0.04 0.05 0.02 0.03 0.09 0.05 0.02 0.06 0.07 0.07SEQID-02651 Q3S0E1 — — 1 0.53 0.23 0.05 0.05 0.05 0.07 0.02 0.02 0.050.04 0.04 0.08 0.11 0.09 SEQID-02652 Q10Q18 — — 1 0.53 0.29 0.05 0.080.04 0.02 0.01 0.04 0.05 0.05 0.02 0.09 0.13 0.04 SEQID-02653 Q62702 — —1 0.43 0.18 0.07 0.09 0.03 0.06 0.02 0.03 0.07 0.04 0.02 0.05 0.06 0.07SEQID-02654 Q2Q511 — — 1 0.49 0.18 0.04 0.06 0.04 0.06 0.02 0.03 0.100.04 0.01 0.05 0.07 0.11 SEQID-02655 Q9SLX0 — — 1 0.42 0.23 0.07 0.070.06 0.06 0.02 0.07 0.09 0.03 0.02 0.06 0.11 0.06 SEQID-02656 Q0IMT5 — —1 0.37 0.16 0.09 0.14 0.02 0.05 0.02 0.03 0.07 0.06 0.02 0.04 0.06 0.04SEQID-02657 Q5QMK7 — — 1 0.47 0.22 0.06 0.07 0.04 0.08 0.01 0.03 0.070.05 0.03 0.05 0.09 0.07 SEQID-02658 Q9LGA3 — — 1 0.46 0.22 0.09 0.070.03 0.06 0.01 0.05 0.06 0.03 0.02 0.04 0.10 0.09 SEQID-02659 Q10MW3 — —1 0.44 0.22 0.07 0.05 0.05 0.05 0.03 0.03 0.07 0.05 0.03 0.06 0.09 0.06SEQID-02660 Q6K4K9 — — 1 0.46 0.28 0.06 0.07 0.03 0.06 0.02 0.06 0.090.02 0.02 0.07 0.13 0.05 SEQID-02661 Q75GT3 — — 1 0.42 0.22 0.06 0.110.03 0.07 0.00 0.06 0.10 0.04 0.01 0.06 0.09 0.07 SEQID-02662 Q6ZHP6 — —0 0.35 0.14 0.12 0.10 0.03 0.06 0.00 0.01 0.17 0.09 0.00 0.00 0.08 0.05SEQID-02663 Q0IQK9 — — 0 0.36 0.24 0.18 0.10 0.05 0.02 0.07 0.02 0.000.05 0.01 0.05 0.10 0.05 SEQID-02664 Q6ZGV5 — — 1 0.48 0.20 0.05 0.140.04 0.05 0.01 0.01 0.12 0.03 0.02 0.07 0.06 0.15 SEQID-02665 Q762A6 — —1 0.47 0.19 0.06 0.09 0.05 0.06 0.01 0.01 0.09 0.05 0.01 0.05 0.06 0.16SEQID-02666 Q42980 — — 1 0.50 0.24 0.12 0.06 0.00 0.05 0.00 0.08 0.090.07 0.04 0.05 0.11 0.06 SEQID-02667 C7IYQ9 — — 1 0.46 0.22 0.06 0.110.04 0.04 0.00 0.09 0.05 0.03 0.04 0.05 0.09 0.05 SEQID-02668 Q6H7T1 — —0 0.44 0.18 0.06 0.16 0.02 0.05 0.01 0.02 0.07 0.06 0.03 0.05 0.07 0.09SEQID-02669 Q67VZ0 — — 1 0.40 0.16 0.08 0.10 0.03 0.06 0.03 0.03 0.050.09 0.04 0.02 0.06 0.01 SEQID-02670 Q6ZH98 — — 1 0.49 0.17 0.04 0.070.04 0.05 0.03 0.02 0.06 0.08 0.03 0.04 0.04 0.08 SEQID-02671 P49210 — —1 0.53 0.25 0.04 0.10 0.05 0.05 0.00 0.03 0.07 0.03 0.03 0.08 0.08 0.10SEQID-02672 Q2R4A1 — — 1 0.44 0.23 0.08 0.12 0.06 0.05 0.01 0.04 0.070.02 0.03 0.09 0.07 0.08 SEQID-02673 Q6L502 — — 1 0.46 0.20 0.06 0.080.05 0.09 0.01 0.04 0.05 0.04 0.01 0.09 0.07 0.09 SEQID-02674 Q10P60 — —1 0.39 0.19 0.06 0.16 0.03 0.09 0.00 0.04 0.08 0.04 0.01 0.02 0.07 0.05SEQID-02675 Q9FWV6 — — 1 0.50 0.26 0.11 0.07 0.02 0.03 0.00 0.01 0.030.07 0.04 0.04 0.14 0.01 SEQID-02676 Q10MT8 — — 1 0.41 0.22 0.07 0.060.04 0.03 0.04 0.03 0.08 0.04 0.04 0.03 0.09 0.0

SEQID-02677 P49398 — — 1 0.51 0.22 0.04 0.10 0.05 0.06 0.01 0.03 0.040.04 0.03 0.08 0.08 0.13 SEQID-02678 C7J0T2 — — 1 0.42 0.17 0.05 0.140.03 0.05 0.01 0.03 0.08 0.03 0.05 0.04 0.08 0.03 SEQID-02679 Q69020 — —1 0.42 0.21 0.05 0.11 0.04 0.06 0.02 0.04 0.11 0.04 0.03 0.05 0.10 0.04SEQID-02680 Q10R17 — — 1 0.43 0.23 0.06 0.09 0.03 0.06 0.02 0.03 0.070.06 0.03 0.05 0.10 0.05 SEQID-02681 Q6Z4E4 — — 1 0.46 0.21 0.07 0.070.05 0.06 0.01 0.04 0.06 0.04 0.01 0.06 0.08 0.06 SEQID-02682 Q10RW9 — —0 0.48 0.25 0.08 0.06 0.04 0.06 0.01 0.04 0.10 0.05 0.01 0.07 0.09 0.10SEQID-02683 Q7X9A7 — — 1 0.45 0.26 0.09 0.08 0.03 0.05 0.00 0.04 0.110.04 0.01 0.08 0.09 0.08 SEQID-02684 Q7XV86 — — 1 0.45 0.18 0.05 0.040.03 0.10 0.01 0.02 0.13 0.03 0.02 0.07 0.07 0.13 SEQID-02685 Q7XMP6 — —1 0.48 0.27 0.10 0.08 0.03 0.05 0.01 0.02 0.08 0.05 0.04 0.06 0.10 0.06SEQID-02686 Q0DCI1 — — 1 0.47 0.23 0.07 0.05 0.03 0.05 0.02 0.05 0.060.04 0.04 0.06 0.10 0.07 SEQID-02687 Q0D9G9 — — 1 0.47 0.20 0.03 0.050.03 0.08 0.00 0.03 0.14 0.02 0.01 0.05 0.10 0.13 SEQID-02688 Q0J716 — —1 0.46 0.18 0.04 0.06 0.03 0.07 0.01 0.05 0.09 0.03 0.02 0.05 0.08 0.09SEQID-02689 Q6Z1D6 — — 1 0.44 0.20 0.04 0.07 0.05 0.08 0.01 0.04 0.100.03 0.04 0.05 0.07 0.06 SEQID-02690 Q10ST8 — — 0 0.37 0.20 0.13 0.100.04 0.01 0.10 0.05 0.00 0.08 0.01 0.02 0.07 0.04 SEQID-02691 Q0DT04 — —1 0.40 0.18 0.09 0.09 0.00 0.08 0.01 0.04 0.06 0.04 0.03 0.04 0.04 0.04SEQID-02692 Q384ZP1 — — 1 0.52 0.25 0.02 0.12 0.04 0.04 0.01 0.03 0.070.05 0.03 0.08 0.08 0.10 SEQID-02693 Q10EK7 — — 0 0.43 0.24 0.14 0.080.01 0.03 0.00 0.09 0.09 0.08 0.02 0.03 0.14 0.03 SEQID-02694 Q2QXN5 — —1 0.45 0.20 0.06 0.18 0.03 0.05 0.01 0.02 0.05 0.03 0.03 0.05 0.05 0.13SEQID-02695 Q0JAI2 — — 1 0.50 0.26 0.06 0.07 0.03 0.07 0.01 0.04 0.080.04 0.01 0.08 0.07 0.14 SEQID-02696 Q2QQ48 — — 0 0.49 0.20 0.04 0.040.05 0.09 0.02 0.04 0.08 0.04 0.05 0.07 0.06 0.11 SEQID-02697 Q7XXS55 —— 1 0.46 0.325 0.07 0.10 0.02 0.08 0.02 0.04 0.06 0.05 0.05 0.04 0.130.06 SEQID-02698 Q0DK10 — — 1 0.44 0.20 0.03 0.13 0.03 0.03 0.01 0.060.09 0.04 0.01 0.05 0.07 0.10 SEQID-02699 Q943F3 — — 1 0.53 0.15 0.030.12 0.05 0.02 0.01 0.04 0.04 0.02 0.04 0.05 0.06 0.13 SEQID-02700Q1DMS5 — — 0 0.47 0.22 0.05 0.13 0.04 0.05 0.00 0.03 0.09 0.02 0.02 0.060.07 0.12 SEQID-02701 Q2R1J8 — — 1 0.43 0.20 0.03 0.17 0.05 0.04 0.000.03 0.09 0.04 0.04 0.04 0.10 0.08 SEQID-02702 Q6YY64 — — 1 0.51 0.180.07 0.09 0.02 0.07 0.00 0.02 0.05 0.04 0.02 0.05 0.08 0.16 SEQID-02703Q6H6I1 — — 1 0.42 0.19 0.13 0.08 0.02 0.04 0.03 0.01 0.06 0.05 0.03 0.050.06 0.05 SEQID-02704 Q6YTX5 — — 1 0.42 0.25 0.16 0.06 0.02 0.04 0.000.02 0.06 0.03 0.04 0.03 0.12 0.05 SEQID-02705 Q6ER94 — — 1 0.44 0.220.07 0.06 0.02 0.08 0.01 0.03 0.05 0.03 0.01 0.07 0.09 0.07 SEQID-02706P52428 — — 1 0.39 0.18 0.09 0.09 0.03 0.06 0.02 0.05 0.09 0.03 0.02 0.040.08 0.05 SEQID-02707 Q8H5N9 — — 1 0.51 0.25 0.11 0.05 0.03 0.03 0.010.02 0.03 0.07 0.03 0.09 0.08 0.04 SEQID-02708 Q0E3

7 — — 1 0.53 0.27 0.10 0.03 0.02 0.04 0.01 0.01 0.04 0.06 0.01 0.10 0.100.05 SEQID-02709 Q2R8Z5 — — 1 0.51 0.22 0.06 0.05 0.05 0.04 0.03 0.020.09 0.05 0.04 0.07 0.06 0.08 SEQID-02710 Q8H8T0 — — 1 0.48 0.19 0.040.06 0.04 0.08 0.02 0.03 0.05 0.03 0.02 0.06 0.08 0.08 SEQID-02711Q85059 — — 1 0.46 0.19 0.06 0.10 0.03 0.08 0.01 0.04 0.07 0.03 0.03 0.050.09 0.07 SEQID-02712 Q5JK10 — — 1 0.45 0.24 0.08 0.06 0.03 0.07 0.010.04 0.06 0.03 0.01 0.06 0.10 0.098 SEQID-02713 Q67UF5 — — 1 0.46 0.210.08 0.03 0.04 0.05 0.02 0.04 0.10 0.04 0.01 0.03 0.10 0.11 SEQID-02714Q0DJG7 — — 1 0.47 0.21 0.04 0.05 0.04 0.08 0.02 0.03 0.06 0.04 0.03 0.040.10 0.08 SEQID-02715 Q8R2W7 — — 1 0.46 0.21 0.04 0.05 0.03 0.07 0.020.04 0.06 0.06 0.05 0.04 0.10 0.06 SEQID-02716 Q6AVT2 — — 1 0.44 0.220.07 0.10 0.05 0.08 0.01 0.03 0.05 0.05 0.01 0.08 0.08 0.06 SEQID-02717Q0JK67 — — 1 0.42 0.21 0.07 0.10 0.04 0.07 0.02 0.03 0.05 0.04 0.03 0.050.10 0.03 SEQID-02718 Q0JP92 — — 1 0.48 0.28 0.06 0.06 0.06 0.05 0.010.06 0.06 0.02 0.01 0.07 0.12 0.04 SEQID-02719 Q654U8 — — 1 0.45 0.210.06 0.05 0.04 0.05 0.02 0.04 0.08 0.05 0.03 0.05 0.10 0.08 SEQID-02720Q93VT8 — — 1 0.47 0.23 0.05 0.06 0.03 0.05 0.01 0.05 0.06 0.05 0.02 0.090.08 0.08 SEQID-02721 Q6K2E8 — — 1 0.45 0.23 0.08 0.08 0.03 0.05 0.010.05 0.06 0.04 0.03 0.06 0.09 0.05 SEQID-02722 Q8W1L6 — — 1 0.51 0.260.06 0.07 0.03 0.05 0.01 0.04 0.06 0.05 0.02 0.07 0.11 0.08 SEQID-02723Q9AQZ5 — — 1 0.44 0.18 0.06 0.06 0.04 0.06 0.02 0.05 0.11 0.03 0.01 0.040.07 0.10 SEQID-02724 Q9ZWR4 — — 1 0.45 0.24 0.07 0.05 0.04 0.06 0.020.07 0.09 0.03 0.02 0.06 0.12 0.05 SEQID-02725 P05117 — — 1 0.46 0.230.04 0.03 0.10 0.05 0.03 0.06 0.05 0.04 0.02 0.10 0.05 0.08 SEQID-02726K48249 — — 1 0.46 0.21 0.05 0.07 0.02 0.06 0.01 0.03 0.08 0.04 0.03 0.070.08 0.06 SEQID-02727 P14280 — — 1 0.48 0.22 0.06 0.05 0.05 0.07 0.010.06 0.04 0.03 0.02 0.06 0.08 0.06 SEQID-02728 K4BHR9 — — 1 0.47 0.210.05 0.07 0.02 0.06 0.01 0.03 0.09 0.04 0.03 0.08 0.07 0.06 SEQID-02729P17786 — — 1 0.521 0.21 0.05 0.06 0.03 0.06 0.01 0.03 0.07 0.05 0.030.07 0.06 0.13 SEQID-02730 P09607 — — 1 0.49 0.23 0.06 0.06 0.04 0.070.02 0.05 0.04 0.03 0.02 0.06 0.09 0.08 SEQID-02731 K48JW4 — — 1 0.520.23 0.06 0.05 0.04 0.07 0.01 0.02 0.07 0.04 0.02 0.06 0.06 0.10SEQID-02732 K4CWR4 — — 1 0.50 0.22 0.06 0.05 0.03 0.06 0.02 0.04 0.080.04 0.03 0.06 0.09 0.08 SEQID-02733 K49N62 — — 1 0.48 0.20 0.06 0.070.05 0.06 0.02 0.04 0.05 0.03 0.03 0.05 0.07 0.09 SEQID-02734 K46WA9 — —1 0.52 0.22 0.06 0.05 0.05 0.08 0.01 0.02 0.05 0.05 0.02 0.07 0.06 0.11SEQID-02735 O82575 — — 0 0.58 0.10 0.09 0.00 0.00 0.04 0.00 0.01 0.200.04 0.23 0.04 0.05 0.18 SEQID-02736 O65819 — — 0 0.53 0.17 0.09 0.050.02 0.03 0.00 0.03 0.09 0.02 0.02 0.07 0.05 0.23 SEQID-02737 K4CX83 — —1 0.48 0.23 0.06 0.06 0.04 0.07 0.01 0.03 0.04 0.05 0.03 0.06 0.07 0.08SEQID-02738 P29000 — — 1 0.47 0.21 0.04 0.04 0.04 0.08 0.01 0.05 0.040.04 0.03 0.05 0.09 0.06 SEQID-02739 K4D8N5 — — 1 0.33 0.17 0.02 0.030.07 0.02 0.02 0.02 0.04 0.02 0.02 0.04 0.08 0.03 SEQID-02740 K4CQV5 — —1 0.44 0.22 0.07 0.05 0.05 0.03 0.02 0.05 0.10 0.05 0.01 0.04 0.11 0.09SEQID-02741 P10967 — — 1 0.48 0.21 0.02 0.05 0.03 0.08 0.02 0.05 0.060.03 0.03 0.05 0.10 0.08 SEQID-02742 Q42382 — — 1 0.43 0.23 0.06 0.080.05 0.07 0.01 0.03 0.06 0.04 0.02 0.09 0.09 0.07 SEQID-02743 K4CPX6 — —1 0.51 0.23 0.05 0.05 0.04 0.06 0.02 0.03 0.07 0.04 0.03 0.06 0.10 0.08SEQID-02744 K4D4C8 — — 1 0.38 0.14 0.02 0.03 0.05 0.03 0.02 0.02 0.040.02 0.04 0.03 0.07 0.07 SEQID-02745 K4CL75 — — 1 0.48 0.20 0.05 0.070.04 0.06 0.02 0.04 0.09 0.04 0.02 0.05 0.08 0.08 SEQID-02746 K4ASM0 — —1 0.48 0.22 0.03 0.06 0.06 0.05 0.01 0.03 0.08 0.03 0.04 0.06 0.10 0.07SEQID-02747 K4CBP6 — — 0 0.44 0.14 0.05 0.16 0.03 0.01 0.09 0.01 0.070.03 0.03 0.03 0.06 0.04 SEQID-02748 P14903 — — 0 0.55 0.25 0.03 0.030.05 0.04 0.06 0.05 0.05 0.02 0.00 0.06 0.15 0.08 SEQID-02749 P62980 — —0 0.53 0.18 0.04 0.07 0.03 0.07 0.02 0.06 0.05 0.04 0.03 0.05 0.08 0.19SEQID-02750 K4CUC1 — — 1 0.48 0.23 0.06 0.04 0.04 0.06 0.04 0.03 0.080.0

0.02 0.05 0.10 0.07 SEQID-02751 K4CW40 — — 1 0.46 0.25 0.08 0.05 0.050.06 0.02 0.03 0.07 0.04 0.02 0.06 0.09 0.07 SEQID-02752 K4B6D8 — — 10.49 0.21 0.02 0.03 0.07 0.04 0.01 0.04 0.09 0.03 0.03 0.07 0.10 0.07SEQID-02753 K4D422 — — 1 0.49 0.20 0.03 0.07 0.04 0.04 0.02 0.04 0.150.04 0.02 0.05 0.10 0.09 SEQID-02754 K4BX34 — — 1 0.42 0.21 0.07 0.080.05 0.03 0.01 0.05 0.08 0.04 0.01 0.05 0.10 0.07 SEQID-02755 P24629 — —1 0.46 0.21 0.05 0.06 0.05 0.07 0.01 0.04 0.10 0.04 0.01 0.07 0.07 0.10SEQID-02756 K4AQY8 — — 0 0.42 0.24 0.09 0.10 0.03 0.08 0.00 0.05 0.060.04 0.01 0.06 0.10 0.05 SEQID-02757 K4D338 — — 1 0.49 0.22 0.06 0.060.04 0.06 0.01 0.04 0.08 0.03 0.02 0.06 0.09 0.08 SEQID-02758 K4D8C4 — —1 0.47 0.22 0.05 0.06 0.05 0.06 0.01 0.03 0.06 0.04 0.03 0.05 0.09 0.07SEQID-02759 Q6LB28 — — 0 0.46 0.19 0.08 0.17 0.01 0.03 0.01 0.07 0.060.03 0.03 0.05 0.10 0.12 SEQID-02760 K4B1G1 — — 1 0.50 0.26 0.05 0.070.05 0.04 0.01 0.04 0.05 0.06 0.03 0.08 0.12 0.06 SEQID-02761 K4CI69 — —1 0.44 0.17 0.06 0.07 0.06 0.05 0.04 0.05 0.03 0.03 0.02 0.05 0.07 0.08SEQID-02762 K4D1H0 — — 1 0.34 0.13 0.05 0.09 0.07 0.05 0.05 0.05 0.020.07 0.02 0.05 0.06 0.03 SEQID-02763 P15003 — — 0 0.43 0.22 0.08 0.060.08 0.08 0.03 0.05 0.03 0.04 0.01 0.05 0.10 0.04 SEQID-02764 K4BAW0 — —1 0.43 0.22 0.07 0.07 0.05 0.04 0.01 0.06 0.08 0.04 0.01 0.04 0.10 0.07SEQID-02765 K4CHY3 — — 1 0.52 0.27 0.07 0.03 0.03 0.07 0.00 0.02 0.080.06 0.01 0.05 0.12 0.12 SEQID-02766 Q6SKP4 — — 1 0.54 0.19 0.04 0.090.02 0.03 0.02 0.05 0.06 0.04 0.05 0.05 0.07 0.16 SEQID-02767 K4C711 — —1 0.46 0.23 0.04 0.10 0.03 0.08 0.01 0.07 0.06 0.03 0.01 0.06 0.10 0.05SEQID-02768 P26300 — — 1 0.46 0.22 0.07 0.04 0.05 0.06 0.01 0.04 0.090.05 0.02 0.06 0.089 0.10 SEQID-02769 P49118 — — 1 0.46 0.22 0.05 0.060.05 0.03 0.01 0.04 0.11 0.04 0.01 0.07 0.08 0.11 SEQID-02770 K4BEL1 — —1 0.48 0.20 0.03 0.05 0.04 0.08 0.01 0.03 0.14 0.02 0.01 0.06 0.09 0.13SEQID-02771 K4BVW7 — — 1 0.44 0.17 0.04 0.08 0.06 0.07 0.01 0.02 0.080.04 0.04 0.05 0.06 0.06 SEQID-02772 B1N678 — — 0 0.41 0.13 0.05 0.170.03 0.01 0.10 0.02 0.08 0.04 0.02 0.01 0.07 0.03 SEQID-02773 K4B3H9 — —0 0.22 0.098 0.03 0.16 0.05 0.07 0.01 0.04 0.08 0.22 0.00 0.03 0.02 0.01SEQID-02774 K4BNT4 — — 1 0.59 0.27 0.02 0.01 0.03 0.05 0.02 0.02 0.110.03 0.07 0.12 0.10 0.12 SEQID-02775 K4CWC4 — — 0 0.55 0.25 0.04 0.010.03 0.08 0.01 0.01 0.09 0.05 0.06 0.07 0.09 0.12 SEQID-02776 K4BIL3 — —1 0.49 0.19 0.04 0.06 0.02 0.06 0.03 0.02 0.05 0.06 0.04 0.06 0.07 0.06SEQID-02777 K4ATQ2 — — 1 0.43 0.20 0.04 0.18 0.03 0.05 0.00 0.04 0.080.03 0.03 0.03 0.10 0.09 SEQID-02778 K4BP02 — — 1 0.41 0.17 0.03 0.220.03 0.02 0.01 0.05 0.04 0.04 0.03 0.03 0.07 0.10 SEQID-02779 K4C3V1 — —1 0.45 0.14 0.06 0.19 0.04 0.02 0.00 0.04 0.07 0.03 0.03 0.03 0.07 0.18SEQID-02780 P12670 — — 1 0.41 0.13 0.05 0.06 0.07 0.04 0.07 0.04 0.030.06 0.01 0.03 0.06 0.04 SEQID-02781 P93210 — — 1 0.40 0.20 0.06 0.070.06 0.06 0.01 0.03 0.14 0.02 0.01 0.06 0.10 0.08 SEQID-02782 O65820 — —0 0.52 0.14 0.13 0.04 0.02 0.01 0.00 0.02 0.07 0.00 0.00 0.03 0.04 0.29SEQID-02783 P37213 — — 0 0.52 0.11 0.17 0.04 0.02 0.01 0.00 0.02 0.060.01 0.01 0.02 0.03 0.30 SEQID-02784 Q08451 — — 1 0.52 0.24 0.08 0.060.03 0.03 0.01 0.03 0.04 0.06 0.03 0.08 0.09 0.04 SEQID-02785 K4DA99 — —1 0.54 0.26 0.09 0.05 0.02 0.03 0.01 0.02 0.04 0.06 0.04 0.10 0.08 0.05SEQID-02786 Q3C2L6 — — 1 0.49 0.25 0.06 0.07 0.04 0.06 0.04 0.02 0.070.06 0.03 0.07 0.09 0.06 SEQID-02787 P28032 — — 1 0.51 0.23 0.06 0.050.04 0.05 0.03 0.02 0.08 0.05 0.04 0.06 0.08 0.08 SEQID-02788 K4CL59 — —1 0.47 0.24 0.05 0.06 0.04 0.05 0.01 0.03 0.07 0.04 0.02 0.06 0.10 0.06SEQID-02789 K4ASC2 — — 1 0.50 0.20 0.06 0.06 0.04 0.06 0.01 0.02 0.090.04 0.03 0.07 0.08 0.10 SEQID-02790 K4C285 — — 1 0.50 0.26 0.04 0.040.07 0.07 0.01 0.03 0.06 0.03 0.02 0.07 0.12 0.10 SEQID-02791 K4B8V1 — —1 0.47 0.23 0.06 0.04 0.06 0.04 0.03 0.03 0.07 0.05 0.03 0.07 0.09 0.06SEQID-02792 K4D8S6 — — 1 0.45 0.18 0.06 0.04 0.03 0.05 0.00 0.03 0.170.02 0.01 0.03 0.06 0.11 SEQID-02793 K4C764 — — 1 0.46 0.21 0.06 0.080.03 0.07 0.01 0.03 0.08 0.04 0.02 0.05 0.10 0.07 SEQID-02794 K4BL25 — —1 0.43 0.24 0.06 0.11 0.03 0.07 0.00 0.05 0.11 0.04 0.02 0.05 0.11 0.08SEQID-02795 F6I0I5 — — 1 0.50 0.23 0.04 0.07 0.02 0.05 0.01 0.02 0.080.04 0.04 0.07 0.10 0.06 SEQID-02796 A5B0L2 — — 1 0.47 0.21 0.05 0.070.02 0.06 0.01 0.03 0.09 0.04 0.03 0.08 0.07 0.06 SEQID-02797 A5BXV1 — —1 0.47 0.21 0.05 0.07 0.02 0.06 0.01 0.03 0.09 0.04 0.03 0.07 0.07 0.06SEQID-02798 D7T227 — — 1 0.48 0.22 0.07 0.04 0.06 0.06 0.01 0.04 0.080.05 0.02 0.07 0.08 0.11 SEQID-02799 C5DBS0 — — 1 0.47 0.22 0.05 0.060.04 0.08 0.01 0.03 0.08 0.06 0.04 0.06 0.08 0.08 SEQID-02800 F6H4T7 — —1 0.47 0.21 0.05 0.098 0.03 0.06 0.02 0.04 0.09 0.04 0.02 0.05 0.08 0.08SEQID-02801 F6HKH3 — — 1 0.47 0.23 0.06 0.03 0.06 0.06 0.01 0.04 0.090.05 0.02 0.07 0.08 0.10 SEQID-02802 F6HXK4 — — 1 0.51 0.27 0.06 0.070.04 0.05 0.01 0.03 0.08 0.04 0.02 0.10 0.10 0.06 SEQID-02803 A5C5K3 — —1 0.50 0.22 0.05 0.05 0.03 0.06 0.02 0.04 0.08 0.05 0.03 0.07 0.09 0.09SEQID-02804 F6HNX5 — — 1 0.45 0.20 0.06 0.06 0.05 0.08 0.01 0.04 0.090.04 0.01 0.07 0.07 0.09 SEQID-02805 A5B118 — — 1 0.46 0.22 0.07 0.060.04 0.03 0.02 0.03 0.10 0.05 0.02 0.04 0.11 0.10 SEQID-02806 A5CAF6 — —1 0.53 0.28 0.07 0.04 0.02 0.07 0.00 0.01 0.08 0.06 0.02 0.05 0.13 0.12SEQID-02807 A5AFS1 — — 1 0.52 0.21 0.04 0.06 0.04 0.06 0.01 0.02 0.080.04 0.03 0.07 0.06 0.12 SEQID-02808 A5C0I8 — — 1 0.49 0.23 0.05 0.060.05 0.05 0.09 0.02 0.09 0.05 0.03 0.06 0.07 0.08 SEQID-02809 F6HLD8 — —1 0.45 0.20 0.06 0.06 0.05 0.08 0.01 0.04 0.09 0.04 0.01 0.07 0.07 0.10SEQID-02810 F6HG44 — — 1 0.52 0.23 0.06 0.05 0.04 0.08 0.01 0.01 0.060.04 0.03 0.07 0.06 0.10 SEQID-02811 F6HCG2 — — 1 0.45 0.22 0.04 0.100.04 0.07 0.01 0.03 0.08 0.04 0.03 0.06 0.09 0.06 SEQID-02812 A5C6H7 — —1 0.47 0.22 0.04 0.08 0.04 0.06 0.01 0.04 0.08 0.03 0.04 0.06 0.10 0.05SEQID-02813 F6H0C4 — — 0 0.46 0.12 0.02 0.01 0.00 0.04 0.02 0.02 0.270.03 0.05 0.03 0.04 0.22 SEQID-02814 F6GSG7 — — 1 0.53 0.23 0.06 0.050.04 0.07 0.01 0.01 0.07 0.05 0.03 0.07 0.06 0.10 SEQID-02815 F6HFF7 — —1 0.46 0.20 0.06 0.06 0.04 0.06 0.01 0.03 0.07 0.05 0.02 0.06 0.07 0.08SEQID-02816 F6HXC8 — — 1 0.46 0.20 0.03 0.08 0.03 0.07 0.01 0.04 0.090.04 0.05 0.08 0.07 0.06 SEQID-02817 D7TCM7 — — 1 0.46 0.23 0.03 0.100.03 0.08 0.01 0.07 0.07 0.04 0.01 0.06 0.10 0.05 SEQID-02818 D7TBH4 — —1 0.47 0.24 0.05 0.06 0.04 0.05 0.01 0.05 0.09 0.04 0.02 0.06 0.12 0.08SEQID-02819 F6I407 — — 1 0.45 0.20 0.05 0.04 0.03 0.04 0.01 0.03 0.180.02 0.01 0.04 0.06 0.11 SEQID-02820 D7TQP5 — — 1 0.42 0.21 0.06 0.100.03 0.08 0.02 0.03 0.11 0.04 0.02 0.07 0.08 0.07 SEQID-02821 A5BT28 — —1 0.48 0.22 0.06 0.09 0.05 0.06 0.01 0.03 0.10 0.02 0.04 0.06 0.11 0.09SEQID-02822 F6I2F8 — — 0 0.42 0.25 0.07 0.10 0.03 0.05 0.01 0.05 0.070.04 0.01 0.07 0.11 0.06 SEQID-02823 F6HHU9 — — 1 0.48 0.20 0.04 0.050.02 0.07 0.02 0.02 0.12 0.03 0.03 0.05 0.09 0.10 SEQID-02824 D7T7Y3 — —1 0.46 0.21 0.05 0.07 0.05 0.06 0.01 0.03 0.06 0.04 0.03 0.06 0.08 0.06SEQID-02825 D7SJV3 — — 1 0.47 0.23 0.05 0.06 0.05 0.06 0.01 0.06 0.090.02 0.02 0.06 0.11 0.07 SEQID-02826 F6HMP1 — — 0 0.40 0.08 0.01 0.060.00 0.00 0.00 0.07 0.22 0.18 0.10 0.06 0.02 0.14 SEQID-02827 ASAML5 — —1 0.56 0.23 0.05 0.02 0.02 0.04 0.02 0.04 0.15 0.03 0.03 0.03 0.07 0.12SEQID-02828 D75KR5 — — 1 0.46 0.19 0.06 0.06 0.02 0.06 0.01 0.02 0.110.05 0.03 0.04 0.10 0.10 SEQID-02829 F6H3T7 — — 1 0.46 0.22 0.06 0.070.03 0.05 0.02 0.03 0.07 0.04 0.02 0.06 0.09 0.06 SEQID-02830 D7TJ46 — —1 0.49 0.23 0.07 0.05 0.03 0.05 0.01 0.02 0.10 0.05 0.01 0.07 0.08 0.11SEQID-02831 F6I0H8 — — 1 0.52 0.27 0.04 0.03 0.08 0.05 0.01 0.03 0.80.04 0.02 0.07 0.11 0.11 SEQID-02832 F6HAM6 — — 1 0.46 0.20 0.07 0.070.04 0.05 0.01 0.02 0.08 0.05 0.04 0.06 0.09 0.07 SEQID-02833 F6HMN8 — —1 0.49 0.22 0.06 0.06 0.03 0.06 0.01 0.03 0.08 0.03 0.02 0.06 0.09 0.09SEQID-02834 D7T1R6 — — 1 0.47 0.22 0.05 0.06 0.05 0.06 0.01 0.03 0.070.05 0.03 0.06 0.08 0.07 SEQID-02835 D7TLU7 — — 1 0.50 0.25 0.07 0.040.05 0.03 0.02 0.03 0.10 0.05 0.02 0.06 0.07 0.09 SEQID-02836 F6H5V8 — —0 0.14 0.03 0.01 0.10 0.01 0.06 0.01 0.04 0.17 0.09 0.03 0.01 0.01 0.06SEQID-02837 D7T0U8 — — 1 0.48 0.21 0.07 0.05 0.04 0.06 0.02 0.02 0.050.04 0.02 0.06 0.06 0.09 SEQID-02838 A5AEI5 — — 0 0.52 0.26 0.02 0.070.03 0.08 0.00 0.09 0.08 0.04 0.02 0.09 0.12 0.11 SEQID-02839 F6HGH4 — —1 0.47 0.22 0.05 0.07 0.04 0.06 0.01 0.04 0.08 0.05 0.01 0.07 0.09 0.09SEQID-02840 F6GV71 — — 1 0.45 0.23 0.06 0.05 0.06 0.04 0.04 0.04 0.070.04 0.03 0.07 0.08 0.06 SEQID-02841 F6HL03 — — 1 0.48 0.20 0.05 0.060.05 0.06 0.02 0.04 0.07 0.05 0.04 0.05 0.08 0.06 SEQID-02842 D75QC6 — —1 0.45 0.17 0.04 0.07 0.03 0.05 0.01 0.05 0.10 0.03 0.02 0.05 0.07 0.09SEQID-02843 A5B878 — — 1 0.51 0.23 0.09 0.07 0.04 0.04 0.00 0.02 0.090.06 0.03 0.10 0.06 0.08 SEQID-02844 A5AKD3 — — 1 0.52 0.17 0.05 0.040.04 0.04 0.02 0.02 0.05 0.09 0.04 0.05 0.04 0.09 SEQID-02845 A5BQN6 — —1 0.50 0.17 0.04 0.07 0.03 0.06 0.02 0.03 0.07 0.08 0.03 0.06 0.04 0.08SEQID-02846 Q9M4H7 — — 0 0.31 0.12 0.12 0.00 0.01 0.04 0.00 0.03 0.360.00 0.00 0.00 0.01 0.10 SEQID-02847 F6HUD1 — — 1 0.47 0.20 0.04 0.020.05 0.07 0.02 0.05 0.06 0.04 0.01 0.06 0.09 0.12 SEQID-02848 C5DB51 — —1 0.51 0.26 0.06 0.07 0.04 0.06 0.02 0.02 0.08 0.04 0.01 0.08 0.10 0.09SEQID-02849 D7TA34 — — 1 0.49 0.22 0.05 0.06 0.06 0.05 0.01 0.03 0.100.03 0.03 0.06 0.08 0.08 SEQID-02850 F6H0X3 — — 1 0.38 0.19 0.08 0.090.03 0.07 0.01 0.03 0.14 0.02 0.01 0.06 0.10 0.07 SEQID-02851 D75UQ2 — —1 0.49 0.20 0.04 0.07 0.05 0.05 0.02 0.05 0.06 0.02 0.04 0.06 0.10 0.09SEQID-02852 D7FBC0 — — 1 0.47 0.25 0.08 0.05 0.05 0.05 0.02 0.04 0.070.04 0.03 0.06 0.09 0.07 SEQID-02853 F6HFL6 — — 1 0.42 0.20 0.07 0.070.04 0.03 0.01 0.06 0.08 0.04 0.01 0.04 0.09 0.07 SEQID-02854 D7TBL7 — —1 0.46 0.23 0.06 0.08 0.04 0.06 0.01 0.04 0.05 0.04 0.03 0.07 0.10 0.05SEQID-02855 F6H1L2 — — 1 0.42 0.17 0.04 0.07 0.05 0.06 0.02 0.05 0.090.04 0.02 0.04 0.07 0.04 SEQID-02856 F6HLZ6 — — 1 0.43 0.18 0.04 0.070.05 0.06 0.02 0.05 0.10 0.04 0.02 0.04 0.038 0.04 SEQID-02857 D7TVX5 —— 1 0.47 0.21 0.06 0.06 0.05 0.07 0.01 0.05 0.07 0.02 0.02 0.03 0.110.07 SEQID-02858 F6H710 — — 1 0.47 0.23 0.06 0.05 0.03 0.06 0.02 0.040.09 0.04 0.03 0.06 0.09 0.08 SEQID-02859 F6HAU0 — — 1 0.48 0.22 0.040.05 0.04 0.09 0.01 0.03 0.05 0.04 0.03 0.06 0.09 0.03 SEQID-02860D7TJI9 — — 1 0.46 0.23 0.06 0.06 0.05 0.05 0.02 0.03 0.07 0.05 0.03 0.070.08 0.05 SEQID-02861 F6H7B3 — — 1 0.47 0.22 0.05 0.06 0.04 0.08 0.010.04 0.11 0.04 0.01 0.08 0.08 0.11 SEQID-02862 D7TVF4 — — 1 0.49 0.230.03 0.05 0.04 0.05 0.02 0.03 0.09 0.04 0.01 0.07 0.09 0.10 SEQID-02863D7TZ79 — — 1 0.53 0.27 0.08 0.03 0.03 0.04 0.01 0.02 0.05 0.06 0.01 0.090.10 0.05 SEQID-02864 F6H2N7 — — 1 0.45 0.22 0.05 0.10 0.03 0.07 0.010.05 0.09 0.03 0.03 0.06 0.12 0.06 SEQID-02865 F6HQM5 — — 0 0.22 0.090.03 0.16 0.05 0.06 0.01 0.04 0.08 0.19 0.00 0.04 0.03 0.01 SEQID-02866Q9FS43 — — 0 0.52 0.20 0.06 0.02 0.01 0.07 0.02 0.02 0.09 0.05 0.06 0.070.04 0.12 SEQID-02867 F6GX20 — — 1 0.44 0.25 0.04 0.09 0.06 0.06 0.020.04 0.08 0.06 0.01 0.08 0.08 0.06 SEQID-02868 F6HDT7 — — 1 0.42 0.160.04 0.09 0.04 0.10 0.01 0.03 0.10 0.03 0.04 0.03 0.08 0.07 SEQID-02869F6GU22 — — 1 0.40 0.19 0.04 0.03 0.10 0.07 0.07 0.03 0.04 0.07 0.02 0.050.07 0.05 SEQID-02870 A5AX75 — — 1 0.45 0.21 0.06 0.05 0.03 0.05 0.010.04 0.14 0.01 0.02 0.04 0.12 0.08 SEQID-02871 Q0MX16 — — 1 0.53 0.250.08 0.05 0.03 0.03 0.01 0.03 0.05 0.06 0.02 0.09 0.09 0.05 SEQID-02872A5AP38 — — 1 0.42 0.18 0.05 0.07 0.05 0.06 0.01 0.03 0.08 0.06 0.02 0.080.06 0.06 SEQID-02873 D7SZX9 — — 1 0.49 0.24 0.06 0.03 0.04 0.03 0.010.04 0.08 0.05 0.01 0.05 0.11 0.08 SEQID-02874 D7TMY3 — — 1 0.48 0.240.06 0.08 0.03 0.06 0.03 0.03 0.08 0.05 0.03 0.06 0.08 0.06 SEQID-02875D7TCC4 — — 1 0.47 0.23 0.04 0.08 0.02 0.06 0.01 0.03 0.10 0.04 0.02 0.070.08 0.06 SEQID-02876 F6GUN5 — — 1 0.46 0.20 0.08 0.12 0.05 0.04 0.000.03 0.05 0.04 0.02 0.06 0.06 0.12 SEQID-02877 D7TVX4 — — 1 0.47 0.210.03 0.08 0.04 0.06 0.02 0.03 0.07 0.03 0.03 0.04 0.10 0.07 SEQID-02878D7UD99 — — 1 0.44 0.17 0.03 0.10 0.06 0.06 0.01 0.03 0.06 0.03 0.05 0.050.07 0.05 SEQID-02879 F6I0

4 — — 1 0.45 0.17 0.03 0.09 0.06 0.07 0.01 0.03 0.07 0.03 0.05 0.04 0.060.06 SEQID-02880 F6GTT4 — — 1 0.51 0.23 0.03 0.06 0.04 0.06 0.01 0.030.09 0.04 0.02 0.07 0.08 0.10 SEQID-02881 F6GTT2 — — 0 0.44 0.25 0.070.09 0.03 0.05 0.00 0.05 0.08 0.05 0.02 0.07 0.10 0.05 SEQID-02882F6HEU9 — — 1 0.34 0.16 0.05 0.05 0.04 0.06 0.01 0.13 0.03 0.03 0.04 0.040.07 0.03 SEQID-02883 Q4U339 — — 1 0.51 0.28 0.05 0.05 0.01 0.04 0.010.04 0.07 0.05 0.01 0.08 0.13 0.03 SEQID-02884 F6HYG1 — — 1 0.44 0.190.06 0.06 0.04 0.07 0.02 0.05 0.11 0.03 0.02 0.05 0.07 0.09 SEQID-02885F6HFK7 — — 1 0.39 0.18 0.07 0.08 0.04 0.05 0.01 0.09 0.08 0.02 0.02 0.050.10 0.06 SEQID-02886 A58M68 — — 1 0.51 0.21 0.03 0.02 0.02 0.09 0.010.05 0.11 0.04 0.01 0.04 0.11 0.11 SEQID-02887 F6H8W9 — — 1 0.52 0.250.07 0.03 0.04 0.04 0.01 0.05 0.05 0.04 0.02 0.06 0.09 0.08 SEQID-02888A5B3K2 — — 0 0.49 0.18 0.06 0.01 0.02 0.03 0.01 0.01 0.22 0.02 0.00 0.050.05 0.17 SEQID-02889 D7SYA1 — — 1 0.46 0.15 0.05 0.19 0.03 0.02 0.000.03 0.07 0.02 0.03 0.03 0.07 0.18 SEQID-02890 D7U394 — — 1 0.54 0.250.05 0.04 0.03 0.05 0.03 0.03 0.07 0.06 0.03 0.05 0.07 0.08 SEQID-02891D7T745 — — 1 0.46 0.21 0.06 0.06 0.04 0.07 0.02 0.03 0.07 0.04 0.04 0.030.10 0.06 SEQID-02892 A5BIQ8 — — 1 0.48 0.20 0.04 0.14 0.01 0.04 0.010.03 0.07 0.07 0.02 0.05 0.06 0.10 SEQID-02893 Q5PXH0 — — 1 0.53 0.250.08 0.05 0.02 0.04 0.01 0.02 0.03 0.06 0.03 0.09 0.09 0.04 SEQID-02894F6I0K9 — — 1 0.47 0.24 0.05 0.05 0.04 0.05 0.00 0.04 0.08 0.04 0.02 0.100.06 0.09 SEQID-02895 D7U9L9 — — 1 0.46 0.23 0.05 0.08 0.03 0.06 0.010.02 0.10 0.04 0.03 0.08 0.09 0.08 SEQID-02896 A5BIN1 — — 1 0.46 0.220.03 0.09 0.07 0.05 0.01 0.03 0.08 0.04 0.03 0.07 0.08 0.06 SEQID-02897F6GSQ2 — — 1 0.44 0.21 0.05 0.07 0.04 0.05 0.02 0.03 0.08 0.06 0.04 0.080.08 0.06 SEQID-02898 F6GY49 — — 1 0.53 0.17 0.04 0.11 0.01 0.03 0.010.05 0.07 0.04 0.05 0.05 0.05 0.15 SEQID-02899 F6H2P8 — — 1 0.49 0.260.07 0.06 0.03 0.05 0.02 0.03 0.07 0.04 0.02 0.06 0.12 0.08 SEQID-02900F6H7I5 — — 1 0.47 0.24 0.05 0.038 0.03 0.07 0.00 0.03 0.06 0.04 0.020.08 0.07 0.09 SEQID-02901 D7TIZ5 — — 1 0.52 0.26 0.06 0.05 0.03 0.060.01 0.03 0.07 0.03 0.03 0.06 0.10 0.09 SEQID-02902 F6I1W0 — — 1 0.490.22 0.04 0.07 0.05 0.05 0.01 0.02 0.10 0.03 0.02 0.06 0.08 0.07SEQID-02903 F6HXL0 — — 1 0.43 0.22 0.05 0.07 0.03 0.05 0.02 0.05 0.080.04 0.02 0.06 0.09 0.06 SEQID-02904 F6HUX3 — — 1 0.34 0.16 0.03 0.050.05 0.05 0.00 0.12 0.05 0.05 0.03 0.03 0.09 0.04 SEQID-02905 F6HSN5 — —1 0.46 0.23 0.08 0.06 0.03 0.06 0.02 0.03 0.06 0.05 0.02 0.05 0.10 0.06SEQID-02906 F6I6W5 — — 1 0.47 0.23 0.05 0.05 0.04 0.05 0.02 0.06 0.060.04 0.03 0.05 0.12 0.08 SEQID-02907 E0CR04 — — 1 0.47 0.23 0.04 0.060.05 0.05 0.01 0.04 0.07 0.04 0.02 0.06 0.10 0.08 SEQID-02908 F6HCU9 — —1 0.49 0.21 0.03 0.05 0.04 0.07 0.01 0.03 0.14 0.03 0.02 0.06 0.09 0.13SEQID-02909 F6HH37 — — 1 0.34 0.18 0.02 0.04 0.05 0.03 0.02 0.02 0.040.02 0.04 0.04 0.09 0.03 SEQID-02910 F

HES2 — — 0 0.41 0.23 0.05 0.02 0.04 0.09 0.01 0.02 0.20 0.02 0.02 0.040.06 0.10 SEQID-02911 F6GUN0 — — 1 0.44 0.24 0.07 0.06 0.03 0.06 0.020.07 0.09 0.02 0.02 0.05 0.13 0.05 SEQID-02912 A5BAX1 — — 1 0.52 0.200.03 0.02 0.04 0.06 0.02 0.03 0.14 0.03 0.06 0.09 0.07 0.11 SEQID-02913A5C3I9 — — 0 0.50 0.20 0.04 0.04 0.03 0.11 0.02 0.04 0.07 0.05 0.06 0.070.06 0.11 SEQID-02914 A5C718 — — 1 0.46 0.16 0.05 0.08 0.04 0.04 0.030.04 0.05 0.03 0.02 0.05 0.07 0.06 SEQID-02915 D7SJX8 — — 1 0.57 0.220.03 0.04 0.03 0.05 0.00 0.02 0.07 0.07 0.03 0.05 0.10 0.11 SEQID-02916D7UC61 — — 1 0.46 0.15 0.09 0.04 0.04 0.04 0.01 0.02 0.17 0.02 0.01 0.020.06 0.19 SEQID-02917 F6HUH1 — — 1 0.42 0.15 0.03 0.05 0.07 0.07 0.070.03 0.03 0.05 0.01 0.04 0.08 0.04 SEQID-02918 D7T5I6 — — 1 0.44 0.220.06 0.04 0.05 0.06 0.02 0.04 0.11 0.03 0.02 0.06 0.11 0.06 SEQID-02919D7SGX1 — — 1 0.47 0.25 0.06 0.04 0.02 0.09 0.01 0.02 0.11 0.03 0.02 0.070.10 0.10 SEQID-02920 F6GSZ1 — — 0 0.25 0.11 0.05 0.09 0.04 0.07 0.000.03 0.05 0.17 0.01 0.03 0.03 0.02 SEQID-02921 A5B427 — — 1 0.50 0.240.04 0.06 0.04 0.07 0.01 0.00 0.08 0.04 0.05 0.06 0.11 0.05 SEQID-02922F6H6J3 — — 1 0.33 0.18 0.06 0.08 0.02 0.11 0.00 0.04 0.05 0.06 0.02 0.030.07 0.05 SEQID-02923 D7TD80 — — 1 0.49 0.20 0.04 0.05 0.05 0.03 0.010.05 0.10 0.03 0.02 0.06 0.07 0.10 SEQID-02924 F6I229 — — 1 0.46 0.180.06 0.04 0.02 0.06 0.01 0.05 0.08 0.05 0.00 0.04 0.09 0.11 SEQID-02925A5BV59 — — 1 0.50 0.22 0.05 0.08 0.03 0.09 0.02 0.02 0.04 0.04 0.03 0.060.09 0.07 SEQID-02926 D7SJS6 — — 1 0.49 0.26 0.05 0.05 0.03 0.06 0.020.03 0.08 0.04 0.03 0.06 0.11 0.08 SEQID-02927 D7TWQ4 — — 1 0.48 0.220.07 0.05 0.04 0.05 0.01 0.04 0.06 0.04 0.05 0.07 0.09 0.08 SEQID-02928F6GU55 — — 1 0.45 0.20 0.07 0.08 0.04 0.05 0.01 0.05 0.02 0.05 0.02 0.050.09 0.08 SEQID-02929 F6HUT2 — — 1 0.42 0.19 0.06 0.06 0.05 0.06 0.020.06 0.03 0.05 0.03 0.07 0.08 0.04 SEQID-02930 F6HDW4 — — 1 0.49 0.180.04 0.07 0.05 0.05 0.02 0.02 0.10 0.05 0.03 0.07 0.07 0.08 SEQID-02931A5BF93 — — 1 0.49 0.26 0.07 0.05 0.05 0.07 0.02 0.05 0.08 0.05 0.01 0.080.09 0.10 SEQID-02932 F6GZN9 — — 1 0.49 0.19 0.05 0.05 0.04 0.07 0.020.02 0.09 0.03 0.03 0.06 0.08 0.07 SEQID-02933 D7SYS5 — — 1 0.44 0.180.04 0.08 0.04 0.06 0.02 0.03 0.07 0.04 0.02 0.05 0.08 0.06 SEQID-02934F6H955 — — 0 0.41 0.20 0.04 0.07 0.04 0.09 0.02 0.07 0.08 0.06 0.04 0.060.08 0.07 SEQID-02935 F6HKX8 — — 1 0.41 0.19 0.04 0.09 0.02 0.05 0.050.03 0.09 0.04 0.04 0.06 0.06 0.06 SEQID-02936 A5BZF5 — — 1 0.43 0.210.05 0.07 0.04 0.07 0.02 0.04 0.09 0.04 0.03 0.05 0.08 0.05 SEQID-02937D7T5P6 — — 1 0.39 0.17 0.05 0.07 0.04 0.07 0.01 0.03 0.06 0.03 0.02 0.050.07 0.07 SEQID-02938 D7TW33 — — 1 0.45 0.19 0.05 0.04 0.04 0.06 0.030.04 0.07 0.04 0.03 0.03 0.09 0.08 SEQID-02939 P56643 — — 1 0.46 0.190.06 0.09 0.03 0.05 0.02 0.03 0.08 0.05 0.04 0.05 0.09 0.06 SEQID-02940D75TJ8 — — 1 0.45 0.22 0.05 0.08 0.06 0.06 0.02 0.04 0.06 0.05 0.04 0.080.07 0.06 SEQID-02941 D7TK33 — — 1 0.49 0.22 0.04 0.08 0.03 0.07 0.020.03 0.08 0.05 0.06 0.07 0.09 0.05 SEQID-02942 D7SYK8 — — 1 0.47 0.230.06 0.07 0.03 0.05 0.01 0.04 0.07 0.05 0.03 0.08 0.08 0.07 SEQID-02943D7SS06 — — 1 0.46 0.22 0.06 0.07 0.03 0.06 0.01 0.04 0.08 0.04 0.02 0.050.10 0.06 SEQID-02944 D7SH83 — — 1 0.46 0.21 0.06 0.07 0.03 0.06 0.010.04 0.10 0.03 0.03 0.05 0.09 0.09 SEQID-02945 F6HHX2 — — 1 0.43 0.200.05 0.05 0.05 0.05 0.01 0.06 0.08 0.04 0.02 0.04 0.09 0.06 SEQID-02946F6HTM3 — — 1 0.43 0.23 0.06 0.05 0.03 0.04 0.00 0.09 0.21 0.01 0.03 0.040.14 0.10 SEQID-02947 D7SZW5 — — 1 0.48 0.22 0.03 0.03 0.02 0.02 0.020.04 0.10 0.08 0.01 0.03 0.09 0.11 SEQID-02948 A5AQ89 — — 1 0.48 0.230.06 0.02 0.02 0.06 0.02 0.07 0.07 0.07 0.02 0.10 0.09 0.05 SEQID-02949D7TBK8 — — 1 0.52 0.26 0.07 0.03 0.02 0.09 0.01 0.03 0.06 0.05 0.02 0.060.10 0.10 SEQID-02950 A5B7Q8 — — 1 0.44 0.19 0.02 0.07 0.04 0.06 0.020.07 0.10 0.05 0.02 0.06 0.08 0.06 SEQID-02951 D7SIH0 — — 0 0.52 0.220.06 0.06 0.05 0.05 0.01 0.03 0.04 0.03 0.01 0.05 0.09 0.09 SEQID-02952A5BYC0 — — 1 0.47 0.23 0.07 0.06 0.04 0.07 0.01 0.02 0.06 0.04 0.04 0.070.09 0.07 SEQID-02953 D7SPB2 — — 1 0.44 0.22 0.04 0.08 0.04 0.08 0.010.02 0.08 0.03 0.05 0.09 0.07 0.07 SEQID-02954 D7SLS3 — — 1 0.42 0.160.03 0.21 0.04 0.02 0.01 0.04 0.04 0.03 0.04 0.04 0.06 0.10 SEQID-02955D7T475 — — 1 0.52 0.24 0.06 0.02 0.03 0.04 0.01 0.02 0.11 0.04 0.01 0.050.09 0.11 SEQID-02956 D7U7S6 — — 1 0.42 0.20 0.06 0.06 0.05 0.07 0.030.05 0.04 0.03 0.02 0.05 0.10 0.07 SEQID-02957 D7T6Q0 — — 1 0.48 0.220.08 0.02 0.02 0.06 0.02 0.03 0.07 0.05 0.04 0.05 0.08 0.10 SEQID-02958D7TPB9 — — 1 0.50 0.22 0.07 0.03 0.02 0.06 0.02 0.03 0.09 0.04 0.03 0.050.06 0.09 SEQID-02959 F6H4V0 — — 1 0.50 0.19 0.03 0.05 0.03 0.05 0.020.02 0.12 0.03 0.04 0.04 0.09 0.10 SEQID-02960 D7TRL3 — — 0 0.45 0.180.04 0.16 0.02 0.04 0.02 0.05 0.07 0.04 0.00 0.04 0.09 0.15 SEQID-02961D7TU16 — — 1 0.48 0.23 0.07 0.06 0.03 0.09 0.01 0.02 0.08 0.03 0.02 0.050.13 0.09 SEQID-02962 D7UCH9 — — 1 0.56 0.28 0.06 0.04 0.02 0.05 0.010.01 0.06 0.03 0.04 0.09 0.13 0.10 SEQID-02963 E0CQY0 — — 1 0.45 0.160.06 0.05 0.07 0.04 0.03 0.05 0.01 0.06 0.02 0.04 0.05 0.05 SEQID-02964E0CSN8 — — 1 0.45 0.17 0.06 0.07 0.04 0.07 0.02 0.01 0.06 0.05 0.03 0.030.08 0.06 SEQID-02965 D7T4T3 — — 1 0.46 0.22 0.04 0.05 0.03 0.06 0.030.07 0.09 0.04 0.05 0.04 0.09 0.05 SEQID-02966 F6GU78 — — 1 0.43 0.180.03 0.10 0.05 0.08 0.02 0.03 0.11 0.04 0.01 0.03 0.08 0.11 SEQID-02967D75R32 — — 1 0.44 0.19 0.08 0.04 0.05 0.06 0.02 0.06 0.13 0.02 0.02 0.040.11 0.11 SEQID-02968 D7THS4 — — 1 0.49 0.17 0.05 0.02 0.05 0.06 0.020.04 0.06 0.04 0.05 0.05 0.09 0.08 SEQID-02969 F6HQD3 — — 1 0.47 0.210.04 0.07 0.03 0.07 0.02 0.01 0.08 0.04 0.05 0.05 0.08 0.05 SEQID-02970F6GUL7 — — 1 0.50 0.22 0.04 0.11 0.04 0.05 0.01 0.03 0.05 0.05 0.03 0.070.09 0.11 SEQID-02971 F6GX19 — — 1 0.48 0.21 0.04 0.09 0.04 0.07 0.020.02 0.08 0.02 0.04 0.03 0.13 0.07 SEQID-02972 F6HQD6 — — 1 0.49 0.210.05 0.05 0.05 0.06 0.01 0.02 0.07 0.04 0.07 0.04 0.09 0.07 SEQID-02973D7TM77 — — 1 0.47 0.20 0.06 0.03 0.05 0.05 0.03 0.04 0.10 0.04 0.03 0.060.07 0.09 SEQID-02974 F6HKS7 — — 1 0.49 0.20 0.07 0.05 0.03 0.05 0.000.04 0.06 0.05 0.04 0.05 0.10 0.06 SEQID-02975 A5ARE0 — — 1 0.51 0.240.04 0.04 0.04 0.06 0.01 0.02 0.08 0.06 0.02 0.05 0.10 0.08 SEQID-02976D7TVP9 — — 1 0.46 0.19 0.05 0.09 0.04 0.09 0.01 0.04 0.07 0.04 0.05 0.040.09 0.06 SEQID-02977 F6HL98 — — 1 0.50 0.25 0.02 0.05 0.07 0.05 0.030.03 0.03 0.03 0.03 0.05 0.17 0.08 SEQID-02978 F6HBC6 — — 1 0.50 0.220.06 0.04 0.04 0.05 0.01 0.03 0.06 0.05 0.02 0.05 0.11 0.08 SEQID-02979D7TA50 — — 1 0.48 0.23 0.07 0.03 0.02 0.05 0.03 0.04 0.07 0.05 0.04 0.060.09 0.06 SEQID-02980 D7T3J3 — — 1 0.47 0.19 0.05 0.06 0.06 0.07 0.010.03 0.07 0.04 0.04 0.06 0.10 0.06 SEQID-02981 D7TKK5 — — 1 0.49 0.220.05 0.06 0.04 0.07 0.02 0.04 0.10 0.03 0.03 0.08 0.08 0.11 SEQID-02982D7U0Q3 — — 1 0.48 0.24 0.05 0.06 0.04 0.05 0.01 0.04 0.07 0.04 0.02 0.040.11 0.07 SEQID-02983 F6I4H0 — — 1 0.50 0.21 0.05 0.06 0.03 0.08 0.020.03 0.07 0.05 0.04 0.07 0.07 0.08 SEQID-02984 A5ALT5 — — 0 0.41 0.160.03 0.07 0.03 0.07 0.03 0.08 0.11 0.05 0.02 0.04 0.07 0.11 SEQID-02985D7T6C5 — — 0 0.44 0.23 0.05 0.08 0.04 0.09 0.01 0.05 0.10 0.03 0.01 0.070.11 0.09 SEQID-02986 F6H0K6 — — 1 0.43 0.19 0.07 0.06 0.03 0.06 0.010.03 0.08 0.04 0.02 0.04 0.11 0.09 SEQID-02987 F6GY09 — — 1 0.47 0.210.04 0.07 0.06 0.07 0.01 0.04 0.09 0.04 0.02 0.06 0.10 0.08 SEQID-02988F6HK38 — — 1 0.50 0.18 0.05 0.05 0.05 0.04 0.01 0.03 0.10 0.03 0.02 0.050.08 0.12 SEQID-02989 F6HE13 — — 1 0.34 0.14 0.05 0.06 0.05 0.04 0.020.14 0.05 0.05 0.01 0.03 0.06 0.03 SEQID-02990 D7TCZ8 — — 1 0.47 0.190.04 0.07 0.04 0.07 0.01 0.03 0.08 0.04 0.04 0.05 0.09 0.07 SEQID-02991F6GST3 — — 1 0.44 0.22 0.05 0.08 0.04 0.05 0.01 0.04 0.09 0.04 0.02 0.060.10 0.07 SEQID-02992 F6HKF1 — — 1 0.48 0.23 0.04 0.07 0.03 0.07 0.020.05 0.07 0.03 0.02 0.07 0.10 0.09 SEQID-02993 D7U4U5 — — 1 0.44 0.220.04 0.09 0.06 0.05 0.01 0.05 0.03 0.05 0.02 0.07 0.08 0.04 SEQID-02994F6HYJ1 — — 1 0.49 0.24 0.08 0.04 0.03 0.05 0.02 0.02 0.07 0.05 0.02 0.050.11 0.09 SEQID-02995 D7SIX7 — — 1 0.47 0.28 0.06 0.08 0.03 0.07 0.020.05 0.08 0.02 0.02 0.07 0.14 0.05 SEQID-02996 F6H392 — — 1 0.24 0.090.07 0.04 0.04 0.04 0.00 0.15 0.04 0.07 0.01 0.04 0.02 0.03 SEQID-02997E0CSK6 — — 0 0.47 0.24 0.05 0.08 0.05 0.06 0.01 0.05 0.08 0.04 0.03 0.080.10 0.07 SEQID-02998 Q07J21 — — 1 0.55 0.22 0.06 0.05 0.04 0.04 0.000.05 0.03 0.05 0.07 0.06 0.12 0.02 SEQID-02999 E0CQR2 — — 1 0.43 0.160.04 0.07 0.05 0.07 0.01 0.02 0.08 0.04 0.04 0.04 0.07 0.05 SEQID-03000D7SRR6 — — 0 0.34 0.18 0.05 0.08 0.07 0.05 0.01 0.10 0.06 0.06 0.03 0.040.08 0.02 SEQID-03001 D7STT1 — — 1 0.47 0.22 0.06 0.06 0.04 0.06 0.020.04 0.09 0.03 0.02 0.05 0.10 0.06 SEQID-03002 F6HH36 — — 1 0.45 0.210.04 0.07 0.05 0.05 0.02 0.03 0.09 0.03 0.03 0.06 0.09 0.05 SEQID-03003A5AHP0 — — 1 0.49 0.28 0.04 0.07 0.05 0.06 0.02 0.05 0.08 0.02 0.02 0.080.13 0.07 SEQID-03004 F6GUM1 — — 1 0.46 0.21 0.05 0.06 0.06 0.07 0.020.04 0.08 0.03 0.03 0.05 0.10 0.06 SEQID-03005 D7T3A6 — — 1 0.46 0.200.03 0.07 0.04 0.07 0.01 0.06 0.10 0.02 0.04 0.05 0.09 0.08 SEQID-03006

273402 — — 1 0.41 0.17 0.04 0.09 0.06 0.05 0.01 0.08 0.09 0.03 0.03 0.040.09 0.06 SEQID-03007 83173888 — — 0 0.44 0.26 0.02 0.09 0.06 0.04 0.000.07 0.12 0.02 0.02 0.08 0.11 0.07 SEQID-03008 219522337 — — 1 0.48 0.220.06 0.05 0.04 0.06 0.01 0.03 0.08 0.03 0.02 0.06 0.09 0.08 SEQID-03009367460278 — — 1 0.46 0.16 0.05 0.06 0.06 0.08 0.01 0.00 0.05 0.04 0.010.08 0.06 0.09 SEQID-03010 2108286 — — 1 0.39 0.16 0.04 0.08 0.06 0.020.03 0.09 0.11 0.04 0.02 0.03 0.11 0.04 SEQID-03011 3319882 — — 1 0.520.22 0.04 0.05 0.04 0.06 0.01 0.03 0.08 0.04 0.02 0.06 0.07 0.13SEQID-03012 301131212 — — 1 0.47 0.21 0.05 0.07 0.02 0.06 0.01 0.03 0.090.04 0.03 0.08 0.07 0.06 SEQID-03013 21068668 — — 1 0.47 0.22 0.03 0.100.06 0.08 0.00 0.01 0.12 0.01 0.03 0.06 0.09 0.05 SEQID-03014 3021333 —— 1 0.46 0.24 0.08 0.05 0.05 0.04 0.01 0.04 0.09 0.05 0.02 0.05 0.110.08 SEQID-03015 13487787 — — 1 0.43 0.22 0.06 0.08 0.05 0.06 0.01 0.030.06 0.04 0.02 0.09 0.08 0.07 SEQID-03016 3413165 — — 1 0.52 0.25 0.060.05 0.04 0.08 0.01 0.01 0.06 0.04 0.01 0.08 0.08 0.09 SEQID-030173175990 — — 1 0.48 0.22 0.04 0.05 0.04 0.08 0.01 0.02 0.07 0.04 0.030.05 0.10 0.09 SEQID-03018 197089784 — — 1 0.46 0.20 0.06 0.09 0.03 0.060.02 0.03 0.08 0.05 0.04 0.05 0.09 0.06 SEQID-03019 38566732 — — 1 0.520.17 0.03 0.02 0.04 0.04 0.02 0.04 0.06 0.09 0.04 0.05 0.04 0.12SEQID-03020 10334493 — — 1 0.47 0.25 0.07 0.05 0.05 0.05 0.02 0.04 0.070.04 0.03 0.06 0.09 0.07 SEQID-03021 4586588 — — 1 0.53 0.18 0.06 0.070.02 0.06 0.03 0.02 0.07 0.04 0.03 0.09 0.06 0.12 SEQID-03022 148612111— — 1 0.39 0.19 0.07 0.08 0.04 0.07 0.01 0.03 0.14 0.02 0.01 0.06 0.100.07 SEQID-03023 10334503 — — 1 0.46 0.19 0.05 0.06 0.05 0.07 0.02 0.070.07 0.03 0.04 0.05 0.07 0.09 SEQID-03024 4586594 — — 0 0.55 0.26 0.020.05 0.03 0.09 0.00 0.08 0.07 0.03 0.01 0.10 0.10 0.12 SEQID-0302520975622 — — 1 0.53 0.20 0.02 0.02 0.05 0.08 0.02 0.04 0.09 0.03 0.070.05 0.08 0.12 SEQID-03026 228552592 — — 1 0.40 0.19 0.06 0.07 0.05 0.070.01 0.03 0.14 0.02 0.02 0.05 0.09 0.08 SEQID-03027 7208773 — — 1 0.480.24 0.04 0.06 0.04 0.06 0.01 0.05 0.08 0.03 0.03 0.08 0.11 0.07SEQID-03028 3043428 — — 1 0.44 0.24 0.06 0.13 0.06 0.06 0.01 0.04 0.050.02 0.03 0.09 0.07 0.08 SEQID-03029 60219077 — — 1 0.49 0.23 0.05 0.060.04 0.06 0.02 0.04 0.08 0.04 0.02 0.07 0.09 0.07 SEQID-03030 84569909 —— 1 0.44 0.16 0.05 0.09 0.04 0.08 0.11 0.02 0.06 0.03 0.03 0.01 0.090.08 SEQID-03031 7208784 — — 1 0.53 0.19 0.04 0.07 0.03 0.06 0.00 0.030.05 0.04 0.03 0.03 0.08 0.18 SEQID-03032 207008822 — — 0 0.54 0.17 0.080.05 0.02 0.02 0.00 0.02 0.10 0.02 0.02 0.07 0.04 0.23 SEQID-03033499171 — — 0 0.47 0.21 0.06 0.01 0.05 0.04 0.01 0.03 0.11 0.06 0.02 0.060.06 0.13 SEQID-03034 219725672 — — 1 0.43 0.19 0.09 0.07 0.05 0.07 0.010.07 0.06 0.03 0.02 0.09 0.06 0.04 SEQID-03035 315440443 — — 0 0.49 0.090.08 0.04 0.04 0.03 0.00 0.04 0.10 0.08 0.08 0.01 0.01 0.12 SEQID-0303645720184 — — 1 0.49 0.25 0.08 0.09 0.02 0.06 0.02 0.03 0.10 0.03 0.060.05 0.07 0.06 SEQID-03037 4586580 — — 1 0.43 0.19 0.06 0.06 0.07 0.070.02 0.06 0.06 0.03 0.01 0.07 0.07 0.07 SEQID-03038 6469141 — — 1 0.470.22 0.03 0.09 0.07 0.06 0.01 0.03 0.07 0.04 0.03 0.05 0.09 0.07SEQID-03039 6850936 — — 0 0.52 0.28 0.08 0.07 0.04 0.08 0.01 0.05 0.050.03 0.02 0.08 0.12 0.11 SEQID-03040 4586578 — — 1 0.53 0.26 0.06 0.070.05 0.04 0.03 0.01 0.07 0.06 0.01 0.12 0.08 0.08 SEQID-03041 O65759 — —0 0.44 0.23 0.08 0.10 0.05 0.02 0.00 0.04 0.07 0.06 0.02 0.05 0.11 0.11SEQID-03042 O49817 — — 0 0.40 0.03 0.10 0.04 0.03 0.08 0.00 0.17 0.080.04 0.02 0.01 0.01 0.16 SEQID-03043 3928152 — — 1 0.50 0.21 0.04 0.060.04 0.02 0.02 0.04 0.08 0.03 0.02 0.04 0.08 0.08 SEQID-03044 21684781 —— 1 0.43 0.18 0.03 0.08 0.07 0.06 0.01 0.04 0.05 0.04 0.04 0.05 0.090.06 SEQID-03045 K9I869 — — 1 0.50 0.20 0.05 0.06 0.05 0.09 0.00 0.030.05 0.04 0.04 0.06 0.08 0.07 SEQID-03046 K9I432 — — 1 0.54 0.18 0.040.11 0.02 0.04 0.00 0.02 0.06 0.04 0.06 0.05 0.06 0.13 SEQID-03047K9HSF5 — — 1 0.53 0.26 0.06 0.02 0.05 0.05 0.01 0.07 0.06 0.05 0.04 0.070.10 0.09 SEQID-03048 K9HCC6 — — 1 0.49 0.23 0.07 0.04 0.06 0.05 0.010.06 0.04 0.04 0.02 0.08 0.06 0.07 SEQID-03049 K9HXR0 — — 1 0.46 0.210.06 0.08 0.04 0.07 0.00 0.05 0.09 0.03 0.01 0.05 0.08 0.09 SEQID-03050K9HXN3 — — 1 0.49 0.23 0.04 0.07 0.04 0.07 0.01 0.04 0.08 0.04 0.02 0.060.083 0.09 SEQID-03051 K9HHN3 — — 1 0.48 0.20 0.03 0.05 0.05 0.07 0.000.04 0.04 0.04 0.04 0.03 0.09 0.09 SEQID-03052 K9I0P5 — — 1 0.46 0.190.05 0.07 0.06 0.06 0.01 0.01 0.07 0.03 0.04 0.07 0.06 0.07 SEQID-03053K9I1X4 — — 1 0.44 0.24 0.07 0.10 0.03 0.05 0.01 0.05 0.07 0.05 0.01 0.070.10 0.06 SEQID-03054 K9HML4 — — 1 0.45 0.23 0.07 0.07 0.04 0.06 0.010.04 0.08 0.03 0.02 0.06 0.09 0.06 SEQID-03055 KSHHZ0 — — 1 0.46 0.220.06 0.08 0.03 0.06 0.01 0.05 0.07 0.05 0.03 0.07 0.07 0.06 SEQID-03056K9HIT2 — — 1 0.48 0.24 0.06 0.07 0.05 0.06 0.01 0.04 0.07 0.04 0.03 0.060.10 0.08 SEQID-03057 K9HU82 — — 1 0.46 0.21 0.07 0.07 0.02 0.05 0.000.05 0.08 0.04 0.03 0.07 0.07 0.07 SEQID-03058 K9I9C0 — — 1 0.42 0.200.06 0.07 0.05 0.07 0.00 0.04 0.10 0.05 0.01 0.07 0.07 0.08 SEQID-03059K9HD94 — — 1 0.47 0.24 0.05 0.09 0.03 0.05 0.02 0.05 0.09 0.03 0.03 0.080.09 0.06 SEQID-03060 K9ICT4 — — 0 0.42 0.21 0.06 0.11 0.01 0.03 0.010.07 0.11 0.04 0.02 0.04 0.08 0.08 SEQID-03061 K9HUL5 — — 1 0.47 0.230.07 0.03 0.05 0.06 0.00 0.04 0.08 0.05 0.02 0.08 0.09 0.10 SEQID-03062K9H805 — — 1 0.53 0.21 0.05 0.03 0.05 0.04 0.01 0.05 0.07 0.05 0.03 0.070.07 0.08 SEQID-03063 K9HNG2 — — 1 0.45 0.20 0.07 0.15 0.04 0.03 0.010.02 0.04 0.06 0.06 0.07 0.06 0.09 SEQID-03064 K9HUK9 — — 1 0.47 0.220.07 0.07 0.04 0.06 0.01 0.04 0.06 0.04 0.03 0.06 0.10 0.06 SEQID-03065K9IBU7 — — 1 0.53 0.21 0.05 0.05 0.04 0.06 0.01 0.02 0.08 0.05 0.03 0.080.05 0.13 SEQID-03066 K9HFT9 — — 1 0.51 0.20 0.06 0.05 0.05 0.06 0.000.05 0.06 0.04 0.04 0.06 0.09 0.08 SEQID-03067 K9I586 — — 1 0.47 0.210.07 0.07 0.02 0.07 0.01 0.04 0.06 0.06 0.04 0.04 0.09 0.09 SEQID-03068K9HV44 — — 1 0.48 0.21 0.05 0.06 0.04 0.07 0.00 0.03 0.07 0.03 0.01 0.050.10 0.08 SEQID-03069 K9I985 — — 1 0.45 0.22 0.06 0.08 0.05 0.05 0.000.04 0.08 0.03 0.03 0.05 0.11 0.06 SEQID-03070 K9HT30 — — 0 0.47 0.240.08 0.06 0.05 0.05 0.00 0.02 0.09 0.04 0.01 0.06 0.08 0.07 SEQID-03071K9I6L1 — — 1 0.41 0.16 0.07 0.11 0.02 0.07 0.00 0.03 0.12 0.03 0.02 0.040.07 0.12 SEQID-03072 K9H8Q7 — — 1 0.48 0.23 0.06 0.06 0.05 0.07 0.010.02 0.05 0.05 0.02 0.07 0.06 0.09 SEQID-03073 K9HRA9 — — 1 0.46 0.210.05 0.07 0.03 0.05 0.02 0.04 0.09 0.04 0.03 0.07 0.09 0.06 SEQID-03074K9HDW7 — — 1 0.45 0.20 0.06 0.06 0.03 0.03 0.01 0.05 0.10 0.05 0.02 0.050.09 0.07 SEQID-03075 K9H7U6 — — 1 0.47 0.17 0.05 0.07 0.05 0.08 0.010.05 0.06 0.04 0.05 0.06 0.07 0.07 SEQID-03076 K9HES3 — — 1 0.46 0.210.04 0.08 0.05 0.05 0.01 0.04 0.08 0.03 0.03 0.06 0.10 0.07 SEQID-03077K9HVW3 — — 1 0.51 0.22 0.05 0.13 0.02 0.03 0.01 0.04 0.05 0.03 0.05 0.050.10 0.13 SEQID-03078 K9HRT5 — — 1 0.45 0.21 0.06 0.12 0.05 0.02 0.000.05 0.09 0.03 0.01 0.08 0.08 0.12 SEQID-03079 K9HST7 — — 1 0.46 0.210.07 0.14 0.05 0.03 0.00 0.05 0.04 0.03 0.03 0.04 0.09 0.10 SEQID-03080K9H972 — — 1 0.48 0.22 0.07 0.09 0.03 0.06 0.01 0.04 0.07 0.03 0.04 0.050.11 0.06 SEQID-03081 K9I188 — — 1 0.45 0.19 0.06 0.05 0.05 0.05 0.000.04 0.10 0.03 0.01 0.04 0.09 0.10 SEQID-03082 K9I379 — — 1 0.50 0.240.04 0.07 0.05 0.08 0.01 0.04 0.06 0.03 0.03 0.08 0.10 0.08 SEQID-03083K9H9R8 — — 1 0.44 0.20 0.07 0.06 0.05 0.03 0.01 0.05 0.07 0.05 0.02 0.060.07 0.06 SEQID-03084 K9I8C2 — — 1 0.47 0.25 0.05 0.08 0.05 0.07 0.010.04 0.06 0.04 0.03 0.09 0.09 0.06 SEQID-03085 K9I5N9 — — 1 0.45 0.180.04 0.07 0.05 0.06 0.01 0.04 0.08 0.03 0.04 0.05 0.07 0.06 SEQID-03086K9HMI3 — — 1 0.48 0.23 0.06 0.07 0.03 0.06 0.00 0.04 0.08 0.03 0.02 0.050.10 0.08 SEQID-03087 K9I6J8 — — 1 0.50 0.22 0.06 0.07 0.03 0.05 0.010.01 0.08 0.05 0.03 0.08 0.07 0.08 SEQID-03088 K9HM52 — — 1 0.50 0.230.02 0.15 0.06 0.07 0.01 0.06 0.09 0.04 0.04 0.06 0.09 0.11 SEQID-03089K9I6I9 — — 1 0.51 0.26 0.02 0.12 0.06 0.07 0.01 0.04 0.06 0.04 0.03 0.100.08 0.09 SEQID-03090 K9HF90 — — 1 0.41 0.18 0.04 0.16 0.05 0.04 0.030.04 0.06 0.03 0.02 0.05 0.06 0.10 SEQID-03091 K9H895 — — 1 0.41 0.180.07 0.07 0.03 0.08 0.01 0.04 0.13 0.01 0.02 0.05 0.09 0.07 SEQID-03092K9HYF2 — — 1 0.50 0.19 0.09 0.08 0.03 0.03 0.00 0.06 0.06 0.03 0.02 0.040.08 0.15 SEQID-03093 K9H8Q4 — — 1 0.50 0.28 0.07 0.05 0.05 0.05 0.000.02 0.07 0.05 0.02 0.06 0.12 0.08 SEQID-03094 K9HEE4 — — 1 0.48 0.220.06 0.06 0.05 0.06 0.02 0.03 0.07 0.04 0.04 0.05 0.09 0.07 SEQID-03095K9HUG1 — — 1 0.48 0.19 0.04 0.05 0.04 0.07 0.01 0.05 0.08 0.03 0.05 0.060.08 0.05 SEQID-03096 K9HV61 — — 1 0.45 0.21 0.07 0.06 0.04 0.05 0.000.05 0.06 0.05 0.04 0.06 0.09 0.05 SEQID-03097 K9I1Z8 — — 0 0.51 0.180.03 0.09 0.01 0.06 0.02 0.06 0.04 0.04 0.02 0.07 0.08 0.1

SEQID-03098 K9I4C3 — — 1 0.48 0.20 0.04 0.15 0.03 0.05 0.01 0.06 0.070.05 0.03 0.09 0.06 0.10 SEQID-03099 K9HY15 — — 1 0.42 0.22 0.06 0.190.02 0.05 0.00 0.06 0.08 0.06 0.03 0.06 0.11 0.09 SEQID-03100 K9I3C6 — —1 0.52 0.25 0.05 0.04 0.04 0.05 0.00 0.05 0.08 0.06 0.02 0.07 0.14 0.10SEQID-03101 K9HE77 — — 1 0.48 0.21 0.04 0.15 0.02 0.06 0.01 0.05 0.060.03 0.02 0.07 0.08 0.13 SEQID-03102 K9HMK1 — — 1 0.48 0.19 0.06 0.090.02 0.04 0.00 0.04 0.07 0.04 0.02 0.06 0.08 0.15 SEQID-03103 K9HVM2 — —0 0.48 0.21 0.07 0.07 0.03 0.04 0.00 0.06 0.03 0.07 0.00 0.04 0.09 0.09SEQID-03104 K9I7D4 — — 1 0.49 0.22 0.07 0.05 0.03 0.05 0.01 0.04 0.100.04 0.02 0.06 0.06 0.123 SEQID-03105 K9HVE8 — — 1 0.48 0.22 0.05 0.060.04 0.06 0.01 0.04 0.08 0.06 0.03 0.07 0.07 0.0

SEQID-03106 K9HYK9 — — 1 0.45 0.21 0.06 0.07 0.04 0.08 0.00 0.05 0.080.06 0.02 0.07 0.08 0.03 SEQID-03107 K9H

M1 — — 1 0.51 0.25 0.06 0.07 0.05 0.04 0.01 0.02 0.07 0.03 0.03 0.030.11 0.06 SEQID-03108 K9HE69 — — 1 0.47 0.21 0.06 0.07 0.08 0.02 0.010.09 0.03 0.05 0.02 0.07 0.06 0.02 SEQID-03109 K9HJ57 — — 1 0.37 0.170.06 0.11 0.02 0.09 0.01 0.04 0.13 0.04 0.03 0.06 0.06 0.09 SEQID-03110K9I7S9 — — 1 0.40 0.17 0.02 0.21 0.06 0.02 0.01 0.04 0.03 0.04 0.06 0.040.05 0.10 SEQID-03111 K9I5Q6 — — 1 0.49 0.22 0.04 0.06 0.06 0.05 0.010.05 0.08 0.03 0.05 0.06 0.08 0.07 SEQID-03112 K9HMM0 — — 1 0.47 0.230.06 0.03 0.04 0.03 0.01 0.04 0.06 0.03 0.05 0.06 0.10 0.07 SEQID-03113K9I794 — — 1 0.46 0.17 0.05 0.06 0.05 0.05 0.02 0.04 0.07 0.04 0.05 0.040.09 0.06 SEQID-03114 K9I1B2 — — 1 0.47 0.19 0.04 0.07 0.03 0.06 0.010.06 0.08 0.06 0.02 0.04 0.09 0.09 SEQID-03115 K9I6M4 — — 1 0.47 0.220.04 0.05 0.04 0.07 0.01 0.06 0.13 0.02 0.01 0.07 0.10 0.11 SEQID-03116K9HWR2 — — 1 0.46 0.24 0.06 0.08 0.04 0.07 0.01 0.04 0.06 0.06 0.03 0.060.11 0.06 SEQID-03117 K9HA66 — — 1 0.45 0.20 0.07 0.06 0.05 0.07 0.010.04 0.06 0.05 0.03 0.07 0.08 0.07 SEQID-03118 K9HQF1 — — 1 0.48 0.200.04 0.03 0.04 0.07 0.01 0.04 0.07 0.04 0.03 0.05 0.08 0.06 SEQID-03119K9HZD5 — — 1 0.55 0.18 0.04 0.04 0.05 0.07 0.01 0.04 0.04 0.07 0.03 0.040.05 0.10 SEQID-03120 K9HRRB — — 1 0.52 0.21 0.04 0.05 0.06 0.05 0.020.04 0.09 0.04 0.03 0.06 0.08 0.10 SEQID-03121 K9HM68 — — 1 0.49 0.210.07 0.12 0.00 0.05 0.01 0.04 0.05 0.06 0.01 0.05 0.09 0.10 SEQID-03122K9I509 — — 1 0.45 0.20 0.10 0.07 0.05 0.06 0.01 0.04 0.07 0.06 0.03 0.080.06 0.05 SEQID-03123 K9HMX1 — — 0 0.46 0.27 0.08 0.03 0.03 0.06 0.010.04 0.05 0.05 0.02 0.06 0.11 0.07 SEQID-03124 K9HI03 — — 1 0.43 0.210.06 0.08 0.04 0.05 0.01 0.04 0.10 0.04 0.01 0.07 0.08 0.07 SEQID-03125K9HPE6 — — 1 0.48 0.21 0.05 0.08 0.06 0.05 0.01 0.04 0.07 0.06 0.04 0.070.07 0.06 SEQID-03126 K9HE

5 — — 1 0.44 0.21 0.07 0.07 0.05 0.06 0.01 0.05 0.06 0.04 0.02 0.05 0.110.07 SEQID-03127 K9H4L4 — — 1 0.52 0.22 0.06 0.06 0.05 0.06 0.01 0.040.06 0.05 0.03 0.08 0.07 0.09 SEQID-03128 K9H4N1 — — 1 0.51 0.22 0.060.04 0.04 0.04 0.01 0.03 0.07 0.06 0.03 0.07 0.07 0.09 SEQID-03129K9HK61 — — 1 0.50 0.20 0.06 0.05 0.04 0.05 0.01 0.03 0.07 0.05 0.05 0.060.09 0.06 SEQID-03130 K9HQA9 — — 1 0.53 0.26 0.05 0.07 0.02 0.02 0.020.04 0.06 0.06 0.03 0.08 0.11 0.05 SEQID-03131 K9HAR9 — — 1 0.45 0.220.05 0.09 0.03 0.07 0.01 0.03 0.08 0.05 0.02 0.06 0.10 0.07 SEQID-03132K9I219 — — 1 0.46 0.20 0.05 0.03 0.04 0.07 0.01 0.06 0.06 0.04 0.03 0.060.09 0.06 SEQID-03133 K9HC31 — — 1 0.47 0.20 0.04 0.06 0.05 0.05 0.010.04 0.08 0.04 0.04 0.04 0.10 0.06 SEQID-03134 K9HCT6 — — 1 0.42 0.170.04 0.10 0.08 0.04 0.01 0.04 0.08 0.05 0.01 0.05 0.05 0.04 SEQID-03135K9HHW4 — — 1 0.50 0.21 0.06 0.08 0.06 0.02 0.01 0.08 0.09 0.04 0.03 0.050.07 0.02 SEQID-03136 K9HP63 — — 1 0.48 0.21 0.03 0.13 0.04 0.05 0.010.04 0.08 0.02 0.01 0.06 0.08 0.13 SEQID-03137 K9HN29 — — 1 0.50 0.220.04 0.06 0.04 0.08 0.01 0.02 0.06 0.04 0.04 0.05 0.08 0.06 SEQID-03138K9HQ79 — — 1 0.48 0.20 0.05 0.07 0.03 0.08 0.01 0.03 0.07 0.06 0.05 0.060.08 0.08 SEQID-03139 K9HPY6 — — 1 0.47 0.22 0.05 0.03 0.03 0.06 0.010.07 0.07 0.06 0.02 0.06 0.10 0.06 SEQID-03140 K9HJ92 — — 1 0.42 0.190.06 0.03 0.04 0.06 0.01 0.04 0.06 0.04 0.03 0.06 0.08 0.05 SEQID-03141K9I7R9 — — 1 0.50 0.24 0.05 0.06 0.03 0.07 0.01 0.06 0.07 0.05 0.03 0.080.08 0.10 SEQID-03142 K9HJT2 — — 1 0.47 0.22 0.05 0.05 0.06 0.06 0.000.03 0.07 0.05 0.02 0.08 0.08 0.08 SEQID-03143 K9I574 — — 1 0.44 0.200.08 0.05 0.07 0.05 0.01 0.04 0.03 0.04 0.02 0.06 0.08 0.06 SEQID-03144K9HQA4 — — 1 0.43 0.20 0.07 0.08 0.04 0.07 0.02 0.06 0.06 0.05 0.04 0.060.07 0.06 SEQID-03145 K9HZ97 — — 1 0.47 0.21 0.05 0.07 0.05 0.07 0.010.04 0.07 0.04 0.04 0.04 0.11 0.07 SEQID-03146 K9I361 — — 1 0.47 0.240.07 0.08 0.04 0.06 0.01 0.04 0.07 0.04 0.02 0.09 0.09 0.05 SEQID-03147K9HBR0 — — 0 0.41 0.24 0.09 0.05 0.02 0.06 0.02 0.10 0.08 0.03 0.02 0.110.05 0.08 SEQID-03148 K9I7W3 — — 0 0.54 0.18 0.06 0.07 0.04 0.08 0.000.06 0.02 0.06 0.03 0.06 0.06 0.17 SEQID-03149 K9I1Y2 — — 1 0.48 0.290.01 0.14 0.06 0.06 0.01 0.04 0.04 0.05 0.04 0.12 0.08 0.07 SEQID-03150K9HDT0 — — 1 0.42 0.16 0.03 0.11 0.06 0.06 0.02 0.04 0.06 0.04 0.01 0.050.05 0.04 SEQID-03151 K9HT24 — — 1 0.48 0.23 0.07 0.06 0.01 0.08 0.010.04 0.06 0.06 0.02 0.07 0.09 0.09 SEQID-03152 K9I2D5 — — 1 0.47 0.210.04 0.17 0.03 0.03 0.00 0.03 0.06 0.02 0.03 0.07 0.07 0.09 SEQID-03153K9HI94 — — 1 0.45 0.17 0.08 0.14 0.04 0.06 0.00 0.04 0.07 0.06 0.04 0.050.06 0.11 SEQID-03154 K9I5L3 — — 1 0.48 0.25 0.06 0.10 0.05 0.07 0.000.06 0.05 0.03 0.02 0.09

0.09 0.10 SEQID-03155 K9HP79 — — 1 0.46 0.19 0.04 0.03 0.04 0.06 0.000.04 0.07 0.03 0.04 0.07 0.08 0.06 SEQID-03156 K9H767 — — 0 0.46 0.150.05 0.05 0.05 0.05 0.00 0.03 0.07 0.03 0.00 0.03 0.09 0.09 SEQID-03157K9HEU3 — — 1 0.51 0.16 0.07 0.03 0.02 0.03 0.00 0.04 0.07 0.05 0.03 0.060.05 0.0

SEQID-03158 K9HGS4 — — 1 0.51 0.14 0.05 0.06 0.04 0.06 0.00 0.02 0.070.02 0.00 0.06 0.06 0.10 SEQID-03159 K9HNK9 — — 1 0.44 0.19 0.08 0.100.01 0.06 0.01 0.05 0.09 0.04 0.03 0.07 0.06 0.06 SEQID-03160 K9HG05 — —1 0.43 0.23 0.07 0.07 0.04 0.07 0.02 0.05 0.06 0.04 0.01 0.07 0.10 0.05SEQID-03161 K9HVR1 — — 1 0.51 0.20 0.04 0.07 0.03 0.06 0.01 0.04 0.070.04 0.07 0.05 0.07 0.07 SEQID-03162 K9HJD1 — — 1 0.40 0.14 0.06 0.050.03 0.05 0.02 0.09 0.09 0.05 0.06 0.04 0.07 0.09 SEQID-03163 K9HWF5 — —1 0.49 0.22 0.07 0.05 0.03 0.07 0.01 0.04 0.08 0.04 0.01 0.05 0.10 0.12SEQID-03164 K9HFM8 — — 1 0.47 0.24 0.06 0.05 0.05 0.07 0.03 0.03 0.070.05 0.01 0.0

0.09 0.09 SEQID-03165 K9HCU6 — — 1 0.47 0.18 0.05 0.06 0.03 0.05 0.000.04 0.09 0.05 0.03 0.05 0.08 0.09 SEQID-03166 K9I5M1 — — 1 0.46 0.230.05 0.07 0.06 0.07 0.00 0.03 0.07 0.04 0.04 0.07 0.11 0.06 SEQID-03167K9HP80 — — 1 0.47 0.21 0.08 0.04 0.05 0.06 0.01 0.02 0.05 0.04 0.05 0.050.08 0.05 SEQID-03168 K9I3Y1 — — 1 0.48 0.23 0.07 0.05 0.05 0.05 0.010.04 0.07 0.05 0.02 0.0

0.07 0.0

SEQID-03169 K9HRV8 — — 0 0.46 0.24 0.07 0.08 0.03 0.06 0.00 0.05 0.080.05 0.02 0.07 0.09 0.06 SEQID-03170 K9HB49 — — 1 0.43 0.16 0.05 0.090.05 0.06 0.01 0.07 0.06 0.03 0.05 0.04 0.06 0.04 SEQID-03171 K9IB94 — —1 0.47 0.22 0.04 0.07 0.02 0.05 0.02 0.04 0.08 0.04 0.05 0.06 0.09 0.05SEQID-03172 K9I3N1 — — 1 0.49 0.24 0.05 0.06 0.03 0.05 0.01 0.04 0.080.04 0.03 0.06 0.10 0.07 SEQID-03173 K9HP17 — — 1 0.45 0.22 0.06 0.070.04 0.06 0.01 0.04 0.07 0.04 0.02 0.06 0.09 0.06 SEQID-03174 K9HRI9 — —1 0.54 0.24 0.04 0.07 0.02 0.04 0.01 0.02 0.08 0.0

0.04 0.0

0.08 0.15 SEQID-03175 K9HXT8 — — 1 0.52 0.24 0.06 0.13 0.02 0.05 0.000.06 0.06 0.03 0.02 0.07 0.08 0.14 SEQID-03176 K9HZL6 — — 0 0.42 0.220.09 0.13 0.01 0.04 0.01 0.06 0.05 0.05 0.01 0.06 0.08 0.11 SEQID-03177K9HHS6 — — 1 0.51 0.23 0.04 0.12 0.01 0.03 0.00 0.05 0.05 0.03 0.04 0.090.09 0.11 SEQID-03178 K9HJC3 — — 1 0.47 0.25 0.08 0.07 0.03 0.06 0.010.04 0.08 0.04 0.02 0.0

0.08 0.12 SEQID-03179 K9HXR3 — — 1 0.50 0.18 0.04 0.14 0.03 0.05 0.010.04 0.02 0.04 0.02 0.06 0.06 0.13 SEQID-03180 K9I3A2 — — 0 0.50 0.170.09 0.11 0.05 0.07 0.00 0.02 0.04 0.01 0.04 0.05 0.06 0.18 SEQID-03181K9I737 — — 0 0.45 0.17 0.05 0.14 0.05 0.03 0.01 0.04 0.06 0.03 0.06 0.060.02 0.09 SEQID-03182 K9I4D4 — — 0 0.52 0.23 0.05 0.15 0.02 0.04 0.000.02 0.04 0.04 0.05 0.07 0.11 0.13 SEQID-03183 K9HA62 — — 1 0.55 0.260.03 0.06 0.05 0.06 0.01 0.04 0.05 0.03 0.02 0.06 0.13 0.16 SEQID-03184K9H9H7 — — 1 0.57 0.26 0.08 0.06 0.03 0.04 0.02 0.05 0.02 0.03 0.05 0.090.12 0.06 SEQID-03185 K9HVR7 — — 1 0.46 0.21 0.04 0.08 0.04 0.06 0.010.04 0.08 0.04 0.03 0.04 0.07 0.06 SEQID-03186 K9HU08 — — 1 0.49 0.260.05 0.06 0.04 0.0

0.01 0.03 0.07 0.05 0.05 0.06 0.12 0.06 SEQID-03187 K9I3W7 — — 1 0.500.22 0.04 0.0

0.04 0.05 0.00 0.06 0.08 0.03 0.05 0.05 0.09 0.06 SEQID-03188 K9I5W6 — —1 0.42 0.16 0.07 0.07 0.03 0.09

0.02 0.03 0.05 0.06 0.03 0.05 0.06 0.05 SEQID-03189 K9I0

0 — — 1 0.51 0.24 0.05 0.04 0.05 0.06 0.00 0.03 0.07 0.03 0.04 0.05 0.120.09 SEQID-03190 K9HPF6 — — 1 0.48 0.22 0.07 0.04 0.04 0.05 0.01 0.070.12 0.03 0.01 0.09 0.09 0.09 SEQID-03191 K9HZH4 — — 1 0.43 0.25 0.060.08 0.03 0.05 0.01 0.08 0.07 0.04 0.02 0.08 0.07 0.04 SEQID-03192K9H560 — — 1 0.45 0.23 0.04 0.06 0.04 0.04 0.01 0.04 0.09 0.04 0.03 0.080.08 0.07 SEQID-03193 K9HMV4 — — 1 0.45 0.22 0.06 0.05 0.06 0.06 0.010.04 0.09 0.04 0.04 0.06 0.07 0.0

SEQID-03194 K9HNW8 — — 1 0.47 0.17 0.05 0.06 0.05 0.07 0.02 0.03 0.030.04 0.03 0.04 0.07 0.06 SEQID-03195 K9HPX5 — — 1 0.48 0.23 0.06 0.070.04 0.05 0.01 0.03 0.06 0.05 0.02 0.08 0.09 0.07 SEQID-03196 K9HUE6 — —1 0.44 0.24 0.07 0.08 0.04 0.05 0.02 0.05 0.06 0.03 0.04 0.09 0.07 0.04SEQID-03197 K9HUI8 — — 1 0.48 0.20 0.05 0.08 0.02 0.05 0.01 0.03 0.100.04 0.03 0.07 0.08 0.08 SEQID-03198 K9HCR7 — — 1 0.47 0.21 0.07 0.060.03 0.06 0.02 0.03 0.09 0.04 0.07 0.06 0.10 0.06 SEQID-03199 K9HE21 — —1 0.48 0.23 0.04 0.07 0.04 0.06 0.00 0.04 0.08 0.04 0.02 0.06 0.13 0.05SEQID-03200 K9HEI4 — — 1 0.47 0.24 0.06 0.09 0.04 0.06 0.00 0.04 0.070.03 0.04 0.05 0.11 0.05 SEQID-03201 K9HY34 — — 1 0.49 0.21 0.07 0.060.04 0.06 0.01 0.05 0.06 0.06 0.02 0.08 0.08 0.09 SEQID-03202 K9HS49 — —1 0.48 0.20 0.05 0.03 0.03 0.06 0.01 0.06 0.07 0.05 0.03 0.07 0.07 0.07SEQID-03203 K9H5L7 — — 1 0.45 0.22 0.06 0.07 0.06 0.04 0.01 0.05 0.090.03 0.04 0.06 0.10 0.05 SEQID-03204 K9I6Y5 — — 1 0.50 0.20 0.06 0.060.04 0.09 0.01 0.03 0.09 0.05 0.04 0.05 0.07 0.10 SEQID-03205 K9HUY3 — —1 0.46 0.22 0.05 0.07 0.03 0.06 0.01 0.05 0.09 0.04 0.02 0.06 0.08 0.07SEQID-03206 K9ICM5 — — 1 0.49 0.21 0.05 0.05 0.03 0.06 0.00 0.05 0.070.03 0.04 0.06 0.09 0.07 SEQID-03207 K9HFN2 — — 1 0.50 0.17 0.04 0.050.04 0.07 0.01 0.03 0.07 0.04 0.04 0.04 0.07 0.07 SEQID-03208 K9I3M2 — —1 0.46 0.17 0.04 0.07 0.04 0.09 0.01 0.04 0.05 0.03 0.04 0.05 0.07 0.07SEQID-03209 K9HV87 — — 1 0.42 0.17 0.05 0.07 0.06 0.08 0.01 0.04 0.060.05 0.04 0.04 0.07 0.04 SEQID-03210 K9I6W6 — — 1 0.45 0.21 0.05 0.090.05 0.05 0.02 0.06 0.05 0.04 0.03 0.06 0.08 0.06 SEQID-03211 K9HXM7 — —1 0.47 0.22 0.05 0.08 0.04 0.07 0.01 0.03 0.08 0.05 0.02 0.05 0.10 0.07SEQID-03212 K9HBK9 — — 1 0.46 0.24 0.06 0.09 0.03 0.05 0.00 0.03 0.080.04 0.03 0.05 0.10 0.08 SEQID-03213 K9HH69 — — 1 0.43 0.21 0.07 0.080.04 0.06 0.01 0.04 0.08 0.03 0.03 0.05 0.10 0.05 SEQID-03214 K9HKG7 — —0 0.43 0.23 0.04 0.19 0.02 0.03 0.00 0.01 0.05 0.03 0.02 0.03 0.09 0.12SEQID-03215 K9I3L2 — — 1 0.59 0.23 0.08 0.07 0.02 0.04 0.00 0.02 0.030.02 0.05 0.09 0.09 0.21 SEQID-03216 K9HK97 — — 1 0.44 0.20 0.04 0.170.04 0.01 0.00 0.03 0.03 0.05 0.02 0.07 0.06 0.11 SEQID-03217 K9HLM3 — —0 0.43 0.18 0.11 0.18 0.01 0.03 0.00 0.07 0.06 0.02 0.02 0.04 0.10 0.11SEQID-03218 K9HB34 — — 0 0.43 0.21 0.04 0.17 0.04 0.06 0.00 0.04 0.080.02 0.02 0.06 0.098 0.09 SEQID-03219 K9HHM4 — — 1 0.53 0.19 0.03 0.110.04 0.02 0.00 0.02 0.06 0.07 0.08 0.05 0.07 0.12 SEQID-03220 K9I2C7 — —1 0.41 0.14 0.04 0.10 0.03 0.03 0.01 0.03 0.06 0.03 0.01 0.02 0.07 0.07SEQID-03221 K

I0P4 — — 0 0.46 0.23 0.07 0.14 0.01 0.05 0.01 0.04 0.06 0.05 0.03 0.050.08 0.07 SEQID-03222 K9HQL8 — — 0 0.48 0.25 0.04 0.13 0.05 0.05 0.000.05 0.09 0.02 0.02 0.05 0.10 0.10 SEQID-03223 K9HQV1 — — 1 0.43 0.200.05 0.06 0.05 0.07 0.00 0.03 0.09 0.05 0.01 0.07 0.06 0.08 SEQID-03224K9I5G0 — — 1 0.45 0.24 0.04 0.09 0.02 0.06 0.00 0.01 0.09 0.03 0.02 0.070.11 0.07 SEQID-03225 K9ICR1 — — 1 0.47 0.18 0.07 0.19 0.04 0.03 0.000.05 0.06 0.03 0.04 0.05 0.07 0.15 SEQID-03226 K9HNM9 — — 1 0.40 0.150.07 0.16 0.04 0.03 0.00 0.06 0.06 0.04 0.04 0.05 0.07 0.11 SEQID-03227K9HSQ2 — — 1 0.48 0.24 0.04 0.10 0.02 0.06 0.01 0.05 0.07 0.04 0.03 0.060.08 0.03 SEQID-03228 K9HPQ3 — — 1 0.43 0.22 0.07 0.03 0.03 0.05 0.000.03 0.11 0.04 0.03 0.06 0.10 0.08 SEQID-03229 K9H7S5 — — 1 0.50 0.260.06 0.06 0.04 0.06 0.01 0.03 0.07 0.05 0.02 0.06 0.08 0.07 SEQID-03230K9HUD2 — — 1 0.48 0.27 0.07 0.03 0.04 0.06 0.00 0.04 0.06 0.05 0.01 0.070.09 0.07 SEQID-03231 K9HP00 — — 0 0.40 0.18 0.07 0.03 0.04 0.05 0.000.06 0.09 0.04 0.04 0.04 0.09 0.06 SEQID-03232 K9I605 — — 1 0.51 0.260.04 0.05 0.04 0.04 0.00 0.04 0.10 0.04 0.03 0.10 0.11 0.09 SEQID-03233K9HHI3 — — 1 0.48 0.21 0.05 0.11 0.03 0.06 0.01 0.05 0.08 0.02 0.04 0.060.08 0.06 SEQID-03234 K9I

5 — — 1 0.47 0.21 0.03 0.03 0.03 0.06 0.01 0.04 0.09 0.04 0.05 0.06 0.080.04 SEQID-03235 K9HTL8 — — 1 0.46 0.24 0.03 0.10 0.05 0.06 0.01 0.070.09 0.03 0.04 0.08 0.08 0.06 SEQID-03236 K9HZX9 — — 1 0.41 0.18 0.060.03 0.04 0.06 0.09 0.04 0.04 0.06 0.01 0.04 0.08 0.03 SEQID-03237K9HV97 — — 1 0.42 0.18 0.07 0.11 0.05 0.0

0.09 0.02 0.04 0.04 0.03 0.06 0.07 0.03 SEQID-03238 K9HKZ1 — — 1 0.480.25 0.07 0.04 0.04 0.05 0.01 0.07 0.08 0.02 0.00 0.09 0.09 0.06SEQID-03239 K9HNA4 — — 1 0.46 0.20 0.08 0.04 0.04 0.07 0.01 0.07 0.100.03 0.01 0.08 0.09 0.08 SEQID-03240 K9HR04 — — 1 0.46 0.22 0.07 0.090.03 0.05 0.01 0.02 0.08 0.04 0.02 0.05 0.08 0.06 SEQID-03241 K9I209 — —1 0.45 0.16 0.04 0.09 0.03 0.05 0.01 0.03 0.09 0.04 0.05 0.05 0.07 0.05SEQID-03242 K9I4P0 — — 1 0.46 0.23 0.07 0.07 0.04 0.05 0.01 0.02 0.090.04 0.03 0.05 0.10 0.08 SEQID-03243 K9I7A5 — — 1 0.47 0.22 0.06 0.030.03 0.05 0.01 0.05 0.08 0.04 0.03 0.07 0.10 0.06 SEQID-03244 K9HKA6 — —1 0.46 0.17 0.05 0.06 0.05 0.05 0.01 0.07 0.05 0.05 0.03 0.05 0.07 0.04SEQID-03245 K9I1J7 — — 1 0.48 0.20 0.07 0.05 0.04 0.05 0.02 0.03 0.090.05 0.07 0.08 0.08 0.05 SEQID-03246 K9I4A6 — — 1 0.47 0.27 0.05 0.070.04 0.06 0.01 0.05 0.06 0.04 0.03 0.07 0.09 0.06 SEQID-03247 K9HJ05 — —1 0.43 0.20 0.05 0.10 0.04 0.06 0.02 0.04 0.07 0.03 0.04 0.07 0.09 0.05SEQID-03248 K9HP50 — — 1 0.50 0.22 0.05 0.07 0.04 0.07 0.00 0.03 0.060.04 0.03 0.08 0.07 0.07 SEQID-03249 K9HY17 — — 1 0.53 0.30 0.05 0.070.03 0.03 0.01 0.04 0.05 0.04 0.01 0.09 0.14 0.04 SEQID-03250 K9HXU7 — —1 0.47 0.18 0.09 0.05 0.05 0.06 0.00 0.03 0.07 0.04 0.03 0.04 0.08 0.08SEQID-03251 K9I7E8 — — 1 0.43 0.21 0.06 0.09 0.06 0.06 0.01 0.04 0.090.04 0.02 0.05 0.09 0.07 SEQID-03252 K9I783 — — 1 0.49 0.22 0.06 0.070.03 0.05 0.00 0.05 0.10 0.02 0.03 0.05 0.12 0.10 SEQID-03253 K9HBS2 — —1 0.48 0.21 0.05 0.07 0.05 0.06 0.01 0.04 0.08 0.03 0.06 0.06 0.09 0.07SEQID-03254 K9HB75 — — 1 0.45 0.21 0.06 0.03 0.05 0.06 0.01 0.03 0.070.06 0.04 0.03 0.08 0.06 SEQID-03255 K9HWN9 — — 1 0.52 0.25 0.07 0.070.04 0.04 0.01 0.02 0.05 0.04 0.02 0.03 0.10 0.04 SEQID-03256 K9HS66 — —1 0.44 0.19 0.07 0.09 0.03 0.06 0.01 0.04 0.08 0.05 0.05 0.06 0.08 0.05SEQID-03257 K9H5W9 — — 1 0.45 0.20 0.03 0.09 0.03 0.05 0.01 0.05 0.100.03 0.05 0.05 0.10 0.07 SEQID-03258 K9HDE7 — — 1 0.50 0.21 0.06 0.070.02 0.06 0.01 0.02 0.07 0.05 0.05 0.07 0.07 0.07 SEQID-03259 K9HXH0 — —1 0.47 0.21 0.05 0.06 0.05 0.07 0.00 0.04 0.10 0.05 0.02 0.06 0.08 0.09SEQID-03260 K9HJZ1 — — 1 0.53 0.23 0.04 0.06 0.04 0.05 0.00 0.04 0.040.03 0.04 0.07 0.10 0.05 SEQID-03261 K9I493 — — 1 0.42 0.21 0.06 0.100.04 0.09 0.01 0.04 0.09 0.04 0.01 0.07 0.09 0.06 SEQID-03262 K9HTI2 — —1 0.45 0.22 0.06 0.10 0.04 0.06 0.01 0.04 0.07 0.05 0.04 0.07 0.09 0.05SEQID-03263 K9ISB7 — — 1 0.46 0.27 0.05 0.09 0.03 0.06 0.00 0.04 0.060.03 0.02 0.07 0.12 0.05 SEQID-03264 K9HZD7 — — 1 0.48 0.23 0.06 0.070.03 0.06 0.01 0.03 0.07 0.05 0.03 0.03 0.09 0.07 SEQID-03265 K9HS81 — —1 0.49 0.20 0.03 0.06 0.04 0.07 0.01 0.04 0.09 0.03 0.04 0.06 0.09 0.09SEQID-03266 K9I1P6 — — 1 0.49 0.22 0.04 0.09 0.04 0.04 0.01 0.04 0.050.04 0.03 0.07 0.10 0.05 SEQID-03267 K9IB16 — — 1 0.45 0.17 0.06 0.120.03 0.08 0.00 0.05 0.09 0.01 0.05 0.04 0.07 0.07 SEQID-03268 K9HBH5 — —1 0.38 0.16 0.09 0.17 0.06 0.03 0.04 0.00 0.05 0.04 0.03 0.06 0.01 0.12SEQID-03269 K9HG97 — — 0 0.41 0.23 0.09 0.09 0.04 0.03 0.00 0.05 0.080.08 0.03 0.04 0.12 0.13 SEQID-03270 K9HJ84 — — 1 0.48 0.18 0.05 0.090.04 0.03 0.02 0.02 0.10 0.04 0.02 0.03 0.09 0.11 SEQID-03271 K9HNE7 — —1 0.42 0.21 0.09 0.04 0.06 0.07 0.06 0.05 0.00 0.04 0.03 0.03 0.05 0.04SEQID-03272 K9HE11 — — 0 0.48 0.15 0.10 0.06 0.02 0.02 0.00 0.02 0.070.03 0.02 0.07 0.04 0.19 SEQID-03273 K9HHP1 — — 1 0.44 0.18 0.04 0.090.04 0.08 0.02 0.02 0.03 0.03 0.02 0.07 0.08 0.05 SEQID-03274 K9HIA6 — —1 0.55 0.27 0.04 0.02 0.04 0.04 0.01 0.02 0.10 0.03 0.06 0.10 0.12 0.11SEQID-03275 K9HNG3 — — 1 0.48 0.21 0.04 0.12 0.06 0.04 0.01 0.02 0.060.06 0.01 0.04 0.08 0.17 SEQID-03276 K9H7R8 — — 1 0.46 0.13 0.07 0.170.01 0.02 0.00 0.08 0.05 0.04 0.02 0.05 0.04 0.17 SEQID-03277 K9HK80 — —0 0.41 0.20 0.08 0.0

0.03 0.04 0.02 0.02 0.09 0.05 0.00 0.07 0.09 0.06 SEQID-03278 K9HT12 — —1 0.40 0.17 0.05 0.12 0.03 0.04 0.00 0.05 0.09 0.05 0.02 0.04 0.08 0.09SEQID-03279 K9HZV3 — — 1 0.50 0.16 0.03 0.04 0.04 0.05 0.00 0.03 0.070.05 0.02 0.04 0.07 0.05 SEQID-03280 K9IGL3 — — 0 0.48 0.19 0.05 0.020.04 0.09 0.01 0.03 0.10 0.03 0.00 0.04 0.08 0.12 SEQID-03281 K9H6B7 — —1 0.41 0.19 0.07 0.12 0.05 0.06 0.01 0.04 0.04 0.03 0.01 0.06 0.12 0.04SEQID-03282 K9HB61 — — 0 0.48 0.23 0.05 0.09 0.03 0.04 0.01 0.06 0.070.02 0.01 0.05 0.12 0.09 SEQID-03283 K9I5V8 — — 1 0.44 0.23 0.05 0.110.04 0.09 0.01 0.05 0.04 0.03 0.04 0.07 0.07 0.05 SEQID-03284 K9I6Q8 — —1 0.46 0.22 0.06 0.07 0.05 0.06 0.01 0.04 0.07 0.03 0.02 0.07 0.08 0.08SEQID-03285 K9HEZ0 — — 1 0.47 0.23 0.08 0.05 0.03 0.05 0.01 0.04 0.070.04 0.03 0.09 0.08 0.06 SEQID-03286 K9HAI6 — — 1 0.50 0.21 0.098 0.040.07 0.04 0.00 0.04 0.07 0.03 0.06 0.08 0.10 0.0

SEQID-03287 K9HQU8 — — 1 0.44 0.20 0.06 0.07 0.04 0.06 0.02 0.04 0.060.06 0.03 0.06 0.06 0.04 SEQID-03288 K9HRI1 — — 1 0.53 0.20 0.03 0.020.04 0.07 0.00 0.04 0.08 0.02 0.06 0.05 0.09 0.10 SEQID-03289 K9HWB2 — —1 0.46 0.25 0.08 0.06 0.05 0.04 0.01 0.05 0.08 0.04 0.01 0.08 0.07 0.07SEQID-03290 K9I4L8 — — 1 0.41 0.15 0.04 0.06 0.03 0.09

0.00 0.07 0.03 0.09 0.02 0.04 0.06 0.04 SEQID-03291 K9IAZ9 — — 1 0.480.22 0.06 0.07 0.02 0.06 0.01 0.07 0.12 0.03 0.04 0.06 0.09 0.06SEQID-03292 K9HC09 — — 1 0.49 0.20 0.05 0.0

0.05 0.06 0.02 0.03 0.06 0.05 0.02 0.05 0.07 0.06 SEQID-03293 K9KG89 — —0 0.50 0.23 0.06 0.06 0.02 0.04 0.00 0.04 0.07 0.04 0.00 0.07 0.09 0.10SEQID-03294 K9HYS1 — — 1 0.54 0.22 0.07 0.07 0.03 0.02 0.00 0.05 0.010.02 0.02 0.06 0.11 0.05 SEQID-03295 K9H7W0 — — 1 0.45 0.19 0.05 0.070.03 0.06 0.01 0.06 0.07 0.04 0.03 0.05 0.09 0.06 SEQID-03296 K9HZB7 — —1 0.44 0.25 0.08 0.09 0.03 0.05 0.00 0.07 0.08 0.03 0.01 0.08 0.09 0.06SEQID-03297 K9I599 — — 1 0.62 0.29 0.07 0.03 0.02 0.02 0.00 0.02 0.040.03 0.05 0.11 0.12 0.05 SEQID-03298 K9HF28 — — 1 0.44 0.25 0.06 0.110.04 0.05 0.00 0.06 0.07 0.04 0.03 0.06 0.12 0.06 SEQID-03299 K9HS24 — —0 0.47 0.25 0.05 0.06 0.06 0.06 0.01 0.02 0.06 0.05 0.01 0.09 0.10 0.07SEQID-03300 K9HVI9 — — 1 0.54 0.25 0.07 0.04 0.03 0.04 0.00 0.03 0.070.05 0.01 0.07 0.09 0.10 SEQID-03301 K9I0Z6 — — 1 0.45 0.22 0.07 0.080.04 0.04 0.01 0.04 0.09 0.05 0.01 0.08 0.08 0.06 SEQID-03302 K9HG59 — —1 0.47 0.23 0.07 0.05 0.02 0.05 0.03 0.04 0.07 0.05 0.05 0.08 0.07 0.07SEQID-03303 K9HA97 — — 1 0.52 0.30 0.07 0.06 0.04 0.05 0.01 0.02 0.070.04 0.03 0.08 0.16 0.07 SEQID-03304 K9HJX8 — — 1 0.47 0.25 0.06 0.070.02 0.05 0.02 0.04 0.07 0.05 0.05 0.06 0.10 0.06 SEQID-03305 K9HL00 — —1 0.50 0.23 0.05 0.08 0.03 0.07 0.01 0.02 0.07 0.04 0.05 0.07 0.08 0.07SEQID-03306 K9I4Y2 — — 0 0.46 0.24 0.08 0.05 0.04 0.06 0.01 0.05 0.060.05 0.02 0.08 0.06 0.08 SEQID-03307 K9I6P1 — — 1 0.47 0.19 0.07 0.050.08 0.06 0.01 0.04 0.04 0.03 0.02 0.04 0.11 0.04 SEQID-03308 K9HYS9 — —1 0.46 0.21 0.05 0.07 0.04 0.05 0.01 0.03 0.07 0.05 0.03 0.05 0.09 0.07SEQID-03309 K9HZC3 — — 1 0.47 0.20 0.03 0.10 0.05 0.07 0.00 0.06 0.110.02 0.04 0.06 0.09 0.09 SEQID-03310 K9I376 — — 1 0.46 0.21 0.05 0.070.05 0.04 0.01 0.05 0.05 0.05 0.04 0.06 0.07 0.04 SEQID-03311 K9IA06 — —1 0.43 0.20 0.03 0.10 0.03 0.05 0.01 0.04 0.05 0.03 0.04 0.04 0.10 0.02SEQID-03312 K9HZ98 — — 0 0.46 0.25 0.05 0.10 0.03 0.04 0.01 0.05 0.100.04 0.02 0.07 0.10 0.09 SEQID-03313 K9I4C4 — — 1 0.48 0.25 0.04 0.100.03 0.08 0.01 0.06 0.07 0.03 0.01 0.08 0.09 0.05 SEQID-03314 K9I7S4 — —1 0.44 0.20 0.06 0.08 0.04 0.05 0.00 0.05 0.08 0.05 0.01 0.05 0.08 0.08SEQID-03315 K9I9Q1 — — 1 0.52 0.25 0.06 0.04 0.05 0.06 0.00 0.02 0.080.05 0.02 0.06 0.11 0.12 SEQID-03316 K9I3E2 — — 1 0.50 0.18 0.04 0.050.03 0.04 0.00 0.03 0.08 0.05 0.05 0.04 0.09 0.08 SEQID-03317 K9IBU9 — —1 0.45 0.21 0.07 0.08 0.05 0.05 0.01 0.04 0.06 0.04 0.03 0.06 0.10 0.07SEQID-03318 K9I7V8 — — 1 0.45 0.20 0.09 0.06 0.03 0.06 0.00 0.03 0.080.03 0.01 0.07 0.07 0.09 SEQID-03319 K9HS31 — — 1 0.42 0.19 0.04 0.090.03 0.06 0.01 0.04 0.07 0.04 0.03 0.07 0.07 0.05 SEQID-03320 K9HBKS — —1 0.49 0.24 0.05 0.06 0.04 0.05 0.01 0.03 0.07 0.04 0.06 0.07 0.11 0.06SEQID-03321 K9HS

— — 1 0.47 0.22 0.04 0.10 0.02 0.07 0.00 0.05 0.08 0.04 0.03 0.05 0.110.06 SEQID-03322 K9HY69 — — 1 0.48 0.24 0.06 0.08 0.04 0.06 0.02 0.030.07 0.03 0.01 0.08 0.09 0.07 SEQID-03323 K9I3V1 — — 1 0.47 0.25 0.060.05 0.06 0.05 0.01 0.02 0.08 0.05 0.03 0.08 0.09 0.06 SEQID-03324K9I3X6 — — 1 0.48 0.22 0.05 0.06 0.06 0.05 0.01 0.04 0.07 0.03 0.05 0.060.10 0.06 SEQID-03325 K9H2Q3 — — 1 0.44 0.21 0.07 0.07 0.03 0.05 0.000.04 0.08 0.03 0.04 0.07 0.09 0.06 SEQID-03326 K9HTU2 — — 1 0.47 0.230.08 0.07 0.04 0.04 0.01 0.03 0.08 0.05 0.02 0.05 0.09 0.07 SEQID-03327K9HX91 — — 1 0.46 0.18 0.05 0.08 0.03 0.07 0.01 0.03 0.09 0.03 0.03 0.040.10 0.07 SEQID-03328 K9HZK9 — — 1 0.46 0.21 0.07 0.07 0.05 0.05 0.010.06 0.05 0.05 0.02 0.07 0.08 0.06 SEQID-03329 K9I853 — — 1 0.34 0.170.07 0.04 0.07 0.07 0.03 0.04 0.04 0.05 0.00 0.04 0.08 0.02 SEQID-03330K9I6R8 — — 1 0.48 0.17 0.04 0.04 0.04 0.06 0.01 0.04 0.08 0.04 0.04 0.040.09 0.06 SEQID-03331 K3HIF4 — — 1 0.46 0.19 0.05 0.07 0.04 0.08 0.010.04 0.06 0.03 0.04 0.05 0.09 0.05 SEQID-03332 K9H9TB — — 1 0.49 0.200.06 0.07 0.03 0.05 0.01 0.05 0.06 0.03 0.05 0.05 0.09 0.05 SEQID-03333K9HBVY6 — — 1 0.50 0.22 0.06 0.09 0.03 0.03 0.01 0.04 0.07 0.04 0.010.05 0.12 0.04 SEQID-03334 K9HKC5 — — 1 0.46 0.21 0.07 0.07 0.05 0.070.00 0.04 0.09 0.04 0.02 0.07 0.07 0.09 SEQID-03335 K9HT37 — — 1 0.500.27 0.06 0.08 0.04 0.04 0.01 0.02 0.05 0.04 0.03 0.10 0.09 0.05SEQID-03336 K9HPY2 — — 1 0.48 0.21 0.09 0.05 0.04 0.05 0.01 0.04 0.060.05 0.02 0.06 0.07 0.08 SEQID-03337 K9HWU9 — — 1 0.43 0.20 0.07 0.070.05 0.07 0.01 0.03 0.06 0.05 0.02 0.06 0.07 0.04 SEQID-03338 K9HX18 — —1 0.52 0.24 0.04 0.07 0.04 0.05 0.01 0.04 0.08 0.03 0.04 0.07 0.11 0.04SEQID-03339 K9HZ01 — — 1 0.46 0.22 0.06 0.08 0.05 0.07 0.01 0.04 0.060.03 0.04 0.05 0.10 0.05 SEQID-03340 K9HPA6 — — 1 0.49 0.21 0.05 0.060.05 0.05 0.01 0.04 0.06 0.03 0.02 0.06 0.09 0.07 SEQID-03341 K9HCQ7 — —1 0.46 0.20 0.05 0.09 0.04 0.05 0.01 0.03 0.06 0.05 0.03 0.06 0.08 0.03SEQID-03342 K9IDW4 — — 1 0.45 0.19 0.05 0.09 0.04 0.06 0.01 0.05 0.070.04 0.05 0.05 0.08 0.06 SEQID-03343 K9HZG6 — — 1 0.49 0.20 0.05 0.070.05 0.07 0.01 0.03 0.08 0.03 0.03 0.05 0.09 0.09 SEQID-03344 K9IB19 — —1 0.47 0.20 0.05 0.06 0.03 0.09 0.01 0.03 0.10 0.03 0.03 0.06 0.08 0.08SEQID-03345 K9HB63 — — 1 0.48 0.25 0.07 0.06 0.04 0.05 0.01 0.04 0.070.04 0.02 0.07 0.10 0.07 SEQID-03346 77737588 — — 1 0.49 0.22 0.08 0.050.00 0.04 0.01 0.10 0.02 0.08 0.04 0.05 0.10 0.05 SEQID-03347 77737572 —— 1 0.48 0.21 0.08 0.05 0.00 0.03 0.01 0.10 0.03 0.08 0.04 0.05 0.100.06 SEQID-03348 218319228 — — 1 0.51 0.24 0.05 0.07 0.03 0.05 0.02 0.020.06 0.04 0.01 0.07 0.09 0.05 SEQID-03349 P48417 — — 1 0.47 0.21 0.050.06 0.04 0.05 0.01 0.03 0.07 0.03 0.01 0.05 0.10 0.08 SEQID-0335057118119 — — 1 0.47 0.21 0.05 0.07 0.02 0.06 0.01 0.03 0.09 0.04 0.030.07 0.07 0.06 SEQID-03351 76056895 — — 1 0.39 0.15 0.07 0.11 0.06 0.040.03 0.04 0.06 0.04 0.02 0.05 0.05 0.03 SEQID-03352 41411212 — — 1 0.500.23 0.08 0.04 0.05 0.07 0.02 0.01 0.07 0.05 0.01 0.06 0.06 0.13SEQID-03353 296511511 — — 1 0.47 0.18 0.04 0.10 0.05 0.06 0.00 0.01 0.140.03 0.02 0.05 0.06 0.10 SEQID-03354 20502190 — — 1 0.33 0.14 0.04 0.090.01 0.04 0.04 0.26 0.05 0.06 0.01 0.05 0.05 0.03 SEQID-03355 20502192 —— 1 0.32 0.15 0.04 0.10 0.01 0.05 0.04 0.24 0.05 0.05 0.01 0.04 0.070.04 SEQID-03356 237637012 — — 1 0.45 0.19 0.06 0.09 0.03 0.05 0.02 0.030.09 0.05 0.04 0.04 0.09 0.06 SEQID-03357 P82381 — — 1 0.48 0.20 0.060.12 0.07 0.05 0.03 0.00 0.07 0.04 0.05 0.04 0.03 0.07 SEQID-03358295416082 — — 1 0.47 0.23 0.04 0.22 0.02 0.03 0.00 0.02 0.04 0.07 0.020.07 0.08 0.11 SEQID-03359 257712682 — — 1 0.46 0.23 0.04 0.09 0.03 0.030.01 0.07 0.07 0.04 0.02 0.06 0.10 0.05 SEQID-03360 206981241 — — 1 0.510.16 0.09 0.06 0.04 0.02 0.00 0.02 0.11 0.02 0.02 0.06 0.05 0.23SEQID-03361 77737574 — — 1 0.47 0.25 0.08 0.05 0.01 0.03 0.00 0.10 0.020.07 0.03 0.06 0.11 0.03 SEQID-03362 257712524 — — 1 0.44 0.16 0.06 0.140.04 0.04 0.03 0.05 0.04 0.04 0.03 0.05 0.06 0.11 SEQID-03363 395146536— — 1 0.47 0.21 0.05 0.06 0.03 0.08 0.01 0.03 0.09 0.04 0.02 0.06 0.100.09 SEQID-03364 227304504 — — 1 0.54 0.22 0.04 0.11 0.05 0.05 0.01 0.020.04 0.04 0.04 0.07 0.10 0.13 SEQID-03365 77737580 — — 1 0.51 0.26 0.080.06 0.01 0.03 0.00 0.10 0.01 0.06 0.03 0.07 0.11 0.03 SEQID-03366219922540 — — 1 0.45 0.18 0.06 0.09 0.07 0.03 0.03 0.04 0.02 0.06 0.010.05 0.07 0.03 SEQID-03367 395146556 — — 1 0.45 0.24 0.09 0.06 0.06 0.040.00 0.01 0.06 0.05 0.01 0.08 0.10 0.06 SEQID-03368 395146543 — — 1 0.480.26 0.07 0.04 0.07 0.05 0.01 0.03 0.07 0.06 0.01 0.06 0.10 0.09SEQID-03369 219725692 — — 1 0.42 0.17 0.09 0.07 0.04 0.07 0.01 0.07 0.060.04 0.02 0.07 0.06 0.04 SEQID-03370 290760343 — — 1 0.56 0.24 0.02 0.070.03 0.08 0.03 0.03 0.09 0.04 0.02 0.05 0.14 0.15 SEQID-03371 257672199— — 1 0.43 0.23 0.09 0.10 0.03 0.03 0.01 0.04 0.06 0.06 0.02 0.05 0.110.13 SEQID-03372 77737576 — — 1 0.48 0.26 0.08 0.06 0.01 0.02 0.00 0.100.02 0.07 0.03 0.06 0.11 0.02 SEQID-03373 218339750 — — 1 0.46 0.28 0.060.08 0.05 0.07 0.02 0.04 0.07 0.07 0.02 0.08 0.12 0.04 SEQID-03374218401648 — — 1 0.55 0.21 0.04 0.04 0.03 0.05 0.00 0.02 0.06 0.07 0.040.05 0.10 0.13 SEQID-03375 168304 — — 1 0.52 0.26 0.02 0.07 0.03 0.080.00 0.09 0.08 0.04 0.02 0.10 0.12 0.11 SEQID-03376 296520445 — — 1 0.470.23 0.09 0.07 0.04 0.04 0.01 0.04 0.07 0.06 0.01 0.07 0.06 0.08SEQID-03377 219789721 — — 1 0.48 0.25 0.08 0.05 0.05 0.05 0.02 0.04 0.060.04 0.02 0.06 0.09 0.07 SEQID-03378 295416104 — — 0 0.46 0.24 0.06 0.060.02 0.07 0.00 0.06 0.09 0.05 0.03 0.07 0.09 0.06 SEQID-03379 218573202— — 0 0.48 0.23 0.03 0.07 0.03 0.07 0.02 0.04 0.10 0.03 0.04 0.07 0.100.08 SEQID-03380 291048676 — — 1 0.49 0.25 0.05 0.05 0.05 0.03 0.02 0.050.09 0.06 0.01 0.08 0.09 0.07 SEQID-03381 395146546 — — 1 0.47 0.21 0.050.08 0.04 0.07 0.01 0.04 0.08 0.04 0.04 0.06 0.08 0.07 SEQID-03382M0ZKT2 — — 0 0.45 0.18 0.09 0.17 0.01 0.03 0.01 0.07 0.06 0.03 0.02 0.050.08 0.12 SEQID-03383 M1AMZ0 — — 1 0.54 0.27 0.02 0.04 0.08 0.07 0.020.03 0.04 0.03 0.02 0.07 0.11 0.09 SEQID-03384 M1AMY4 — — 1 0.52 0.270.02 0.04 0.06 0.08 0.02 0.04 0.03 0.03 0.02 0.07 0.10 0.08 SEQID-03385M0ZXL4 — — 0 0.51 0.26 0.02 0.07 0.03 0.08 0.00 0.09 0.08 0.04 0.02 0.090.12 0.10 SEQID-03386 M1AMY9 — — 0 0.57 0.22 0.01 0.05 0.05 0.07 0.020.04 0.04 0.05 0.03 0.07 0.07 0.12 SEQID-03387 M1AKE5 — — 0 0.47 0.270.02 0.05 0.08 0.05 0.04 0.04 0.04 0.04 0.00 0.08 0.12 0.06 SEQID-03388M1AGXS — — 1 0.47 0.20 0.06 0.04 0.06 0.06 0.00 0.05 0.07 0.04 0.02 0.050.10 0.07 SEQID-03389 M1C5FS — — 1 0.48 0.21 0.05 0.07 0.02 0.06 0.010.03 0.09 0.04 0.03 0.07 0.08 0.06 SEQID-03390 M18BVW6 — — 1 0.48 0.220.04 0.06 0.05 0.06 0.00 0.04 0.08 0.03 0.03 0.06 0.11 0.07 SEQID-03391M02HX8 — — 0 0.54 0.17 0.06 0.05 0.02 0.02 0.00 0.02 0.10 0.03 0.02 0.070.05 0.23 SEQID-03392 M02HU8 — — 0 0.47 0.22 0.04 0.21 0.02 0.03 0.000.02 0.05 0.09 0.02 0.07 0.08 0.11 SEQID-03393 J7EQ13 — — 0 0.39 0.160.05 0.03 0.06 0.03 0.10 0.01 0.08 0.05 0.02 0.04 0.07 0.09 SEQID-03394M1B3W0 — — 1 0.48 0.20 0.06 0.02 0.05 0.06 0.00 0.05 0.07 0.02 0.02 0.040.11 0.07 SEQID-03395 09M6H3 — — 1 0.44 0.23 0.06 0.10 0.03 0.07 0.010.03 0.13 0.02 0.03 0.05 0.12 0.08 SEQID-03396 Q8LK04 — — 1 0.51 0.220.06 0.05 0.04 0.08 0.01 0.01 0.07 0.05 0.02 0.06 0.06 0.10 SEQID-03397M1ACZ6 — — 1 0.53 0.24 0.04 0.06 0.05 0.06 0.01 0.02 0.11 0.02 0.03 0.070.08 0.11 SEQID-03398 MQZI18 — — 1 0.45 0.20 0.05 0.06 0.05 0.08 0.010.04 0.10 0.04 0.01 0.07 0.07 0.10 SEQID-03399 M19FJ0 — — 0 0.45 0.190.07 0.07 0.04 0.09 0.00 0.02 0.10 0.01 0.00 0.00 0.14 0.16 SEQID-03400M1B1W6 — — 1 0.52 0.24 0.04 0.08 0.06 0.07 0.00 0.04 0.07 0.03 0.03 0.060.12 0.07 SEQID-03401 M1

QM9 — — 1 0.52 0.21 0.04 0.06 0.03 0.06 0.01 0.03 0.07 0.05 0.03 0.070.06 0.12 SEQID-03402 K7WJX9 — — 0 0.44 0.10 0.06 0.16 0.04 0.01 0.090.00 0.07 0.03 0.03 0.01 0.06 0.03 SEQID-03403 M1CQ57 — — 0 0.45 0.170.06 0.15 0.02 0.05 0.01 0.02 0.07 0.06 0.03 0.06 0.07 0.09 SEQID-03404M0ZVD2 — — 1 0.42 0.20 0.07 0.06 0.05 0.05 0.01 0.04 0.08 0.05 0.01 0.050.11 0.07 SEQID-03405 M161K7 — — 0 0.39 0.22 0.08 0.11 0.06 0.02 0.000.04 0.06 0.08 0.02 0.05 0.11 0.10 SEQID-03406 M1B8F8 — — 0 0.38 0.150.04 0.02 0.04 0.03 0.11 0.02 0.07 0.06 0.03 0.05 0.07 0.08 SEQID-03407M1AVV0 — — 1 0.50 0.24 0.05 0.04 0.03 0.06 0.02 0.03 0.08 0.04 0.02 0.060.09 0.09 SEQID-03408 M1CVH4 — — 1 0.44 0.17 0.04 0.09 0.05 0.07 0.020.03 0.07 0.03 0.05 0.05 0.06 0.06 SEQID-03409 M1CQ02 — — 1 0.49 0.220.06 0.06 0.04 0.06 0.01 0.03 0.08 0.03 0.02 0.06 0.09 0.08 SEQID-03410M16FR3 — — 0 0.48 0.21 0.07 0.11 0.06 0.04 0.02 0.01 0.03 0.06 0.00 0.070.05 0.13 SEQID-03411 M1AMY3 — — 1 0.51 0.26 0.03 0.02 0.10 0.08 0.020.01 0.06 0.03 0.03 0.06 0.11 0.07 SEQID-03412 M0ZI9B — — 1 0.47 0.220.07 0.07 0.05 0.06 0.01 0.03 0.08 0.04 0.04 0.06 0.09 0.08 SEQID-03413M0ZSD6 — — 1 0.47 0.22 0.07 0.04 0.05 0.06 0.01 0.04 0.09 0.05 0.02 0.060.08 0.10 SEQID-03414 M1D7J7 — — 1 0.46 0.23 0.06 0.06 0.04 0.04 0.020.04 0.09 0.04 0.02 0.06 0.11 0.07 SEQID-03415 M0ZSL2 — — 1 0.52 0.260.08 0.03 0.03 0.05 0.01 0.01 0.06 0.06 0.01 0.09 0.11 0.06 SEQID-03416A0Z2Z75 — — 1 0.58 0.21 0.05 0.10 0.08 0.02 0.00 0.00 0.06 0.03 0.080.13 0.06 0.12 SEQID-03417 A1A073 — — 1 0.61 0.15 0.03 0.09 0.02 0.070.00 0.02 0.05 0.04 0.09 0.04 0.02 0.16 SEQID-03418 A1A091 — — 0 0.450.26 0.03 0.13 0.05 0.04 0.00 0.03 0.09 0.03 0.02 0.08 0.08 0.08SEQID-03419 A2WLS0 — — 0 0.37 0.09 0.04 0.00 0.04 0.07 0.16 0.02 0.120.07 0.02 0.02 0.00 0.16 SEQID-03420 A2YN17 — — 1 0.36 0.17 0.05 0.140.01 0.06 0.02 0.05 0.11 0.08 0.04 0.01 0.10 0.06 SEQID-03421 A4GGC8 — —1 0.51 0.24 0.04 0.20 0.06 0.02 0.01 0.04 0.01 0.02 0.03 0.12 0.09 0.10SEQID-03422 A4GYV1 — — 1 0.58 0.21 0.04 0.10 0.10 0.02 0.00 0.00 0.040.03 0.08 0.10 0.09 0.12 SEQID-03423 A5A779 — — 1 0.44 0.24 0.04 0.100.04 0.05 0.03 0.06 0.10 0.01 0.04 0.01 0.18 0.04 SEQID-03424 ASLHG2 — —1 0.36 0.20 0.05 0.26 0.00 0.04 0.02 0.05 0.03 0.04 0.03 0.04 0.15 0.04SEQID-03425 ASVI25 — — 1 0.34 0.15 0.04 0.04 0.03 0.26 0.00 0.03 0.140.02 0.03 0.04 0.07 0.05 SEQID-03426 A5VLV3 — — 1 0.51 0.22 0.04 0.060.03 0.07 0.02 0.01 0.10 0.04 0.05 0.06 0.10 0.09 SEQID-03427 A5YT9S — —1 0.37 0.15 0.04 0.07 0.05 0.05 0.10 0.04 0.10 0.04 0.01 0.03 0.08 0.09SEQID-03428 A6QLV3 — — 1 0.49 0.27 0.03 0.06 0.08 0.04 0.01 0.03 0.090.02 0.03 0.05 0.18 0.10 SEQID-03429 A6QPY8 — — 1 0.50 0.15 0.06 0.040.02 0.03 0.01 0.04 0.08 0.08 0.03 0.04 0.05 0.18 SEQID-03430 A6ZNN4 — —0 0.36 0.04 0.00 0.00 0.02 0.05 0.27 0.02 0.12 0.05 0.04 0.02 0.02 0.18SEQID-03431 A62UT6 — — 1 0.53 0.13 0.03 0.08 0.05 0.10 0.00 0.02 0.080.03 0.04 0.04 0.06 0.23 SEQID-03432 A7Y3J1 — — 1 0.58 0.19 0.03 0.120.06 0.03 0.00 0.00 0.05 0.03 0.09 0.11 0.06 0.13 SEQID-03433 A7YWC8 — —0 0.31 0.22 0.12 0.15 0.01 0.05 0.01 0.09 0.12 0.03 0.02 0.02 0.17 0.01SEQID-03434 B1A958 — — 1 0.43 0.21 0.04 0.27 0.05 0.02 0.01 0.04 0.010.02 0.03 0.11 0.08 0.07 SEQID-03435 B1A969 — — 0 0.40 0.22 0.02 0.320.03 0.00 0.07 0.06 0.03 0.03 0.03 0.15 0.03 0.11 SEQID-03436 B2G634 — —1 0.57 0.24 0.04 0.01 0.05 0.06 0.00 0.03 0.09 0.03 0.03 0.08 0.09 0.12SEQID-03437 B2G729 — — 1 0.41 0.09 0.05 0.05 0.08 0.09 0.00 0.07 0.090.00 0.03 0.04 0.04 0.01 SEQID-03438 B3WC71 — — 1 0.37 0.17 0.04 0.000.06 0.16 0.00 0.05 0.15 0.02 0.01 0.04 0.09 0.03 SEQID-03439 BSY212 — —1 0.45 0.17 0.05 0.05 0.04 0.08 0.06 0.04 0.08 0.04 0.04 0.02 0.07 0.06SEQID-03440 B5X9P2 — — 1 0.44 0.17 0.05 0.05 0.04 0.09 0.06 0.04 0.080.03 0.04 0.02 0.06 0.06 SEQID-03441 B7GNC2 — — 0 0.57 0.29 0.05 0.120.09 0.03 0.00 0.02 0.06 0.03 0.06 0.05 0.10 0.10 SEQID-03442 B7GND6 — —1 0.61 0.15 0.03 0.09 0.02 0.07 0.00 0.02 0.05 0.04 0.08 0.04 0.02 0.17SEQID-03443 B8DW17 — — 1 0.60 0.15 0.03 0.10 0.02 0.07 0.00 0.02 0.040.04 0.09 0.04 0.02 0.15 SEQID-03444 E1BLN6 — — 1 0.23 0.12 0.02 0.110.01 0.02 0.10 0.10 0.06 0.03 0.01 0.02 0.04 0.03 SEQID-03445 E7Q5T7 — —1 0.42 0.19 0.03 0.05 0.07 0.06 0.00 0.06 0.16 0.01 0.02 0.05 0.11 0.11SEQID-03446 F1MUE4 — — 1 0.49 0.24 0.04 0.07 0.03 0.05 0.01 0.05 0.120.03 0.02 0.02 0.16 0.08 SEQID-03447 F1MWJ0 — — 1 0.30 0.18 0.02 0.030.02 0.02 0.03 0.05 0.01 0.12 0.02 0.05 0.07 0.04 SEQID-03448 F1SGG1 — —1 0.40 0.23 0.05 0.11 0.04 0.06 0.00 0.07 0.12 0.03 0.02 0.05 0.13 0.06SEQID-03449 G1NEY4 — — 1 0.38 0.19 0.05 0.10 0.04 0.04 0.00 0.05 0.090.10 0.01 0.04 0.10 0.06 SEQID-03450 G3MXL3 — — 1 0.37 0.18 0.05 0.080.04 0.04 0.01 0.06 0.08 0.12 0.01 0.04 0.09 0.06 SEQID-03451 I3LR13 — —1 0.40 0.19 0.04 0.11 0.02 0.04 0.01 0.07 0.09 0.03 0.04 0.02 0.12 0.02SEQID-03452 O04433 — — 1 0.51 0.14 0.08 0.07 0.01 0.02 0.02 0.03 0.090.02 0.02 0.02 0.07 0.22 SEQID-03453 O42395 — — 1 0.32 0.08 0.04 0.120.03 0.05 0.12 0.03 0.09 0.06 0.06 0.04 0.03 0.08 SEQID-03454 O62650 — —1 0.37 0.15 0.03 0.07 0.05 0.06 0.10 0.04 0.10 0.04 0.01 0.03 0.08 0.09SEQID-03455 P00127 — — 1 0.35 0.14 0.04 0.03 0.02 0.15 0.01 0.06 0.270.02 0.06 0.01 0.07 0.07 SEQID-03456 P02313 — — 0 0.34 0.03 0.12 0.070.04 0.10 0.00 0.04 0.10 0.06 0.00 0.00 0.01 0.29 SEQID-03457 P02314 — —0 0.37 0.03 0.11 0.07 0.04 0.09 0.00 0.04 0.10 0.05 0.00 0.00 0.01 0.30SEQID-03458 P02687 — — 1 0.39 0.10 0.05 0.15 0.01 0.06 0.00 0.06 0.010.08 0.07 0.02 0.06 0.09 SEQID-03459 P04101 — — 0 0.10 0.05 0.02 0.600.00 0.00 0.16 0.00 0.00 0.00 0.02 0.02 0.00 0.00 SEQID-03460 P05016 — —1 0.54 0.27 0.03 0.04 0.07 0.04 0.02 0.03 0.10 0.01 0.02 0.04 0.17 0.10SEQID-03461 P05739 — — 1 0.53 0.23 0.05 0.08 0.04 0.03 0.00 0.04 0.090.02 0.01 0.01 0.11 0.17 SEQID-03462 P07107 — — 1 0.52 0.13 0.06 0.020.02 0.08 0.00 0.03 0.13 0.03 0.03 0.05 0.06 0.19 SEQID-03463 P07924 — —0 0.41 0.20 0.04 0.17 0.03 0.05 0.00 0.09 0.06 0.04 0.04 0.12 0.06 0.09SEQID-03464 P03771 — — 1 0.52 0.17 0.02 0.15 0.09 0.02 0.00 0.06 0.030.02 0.11 0.07 0.07 0.06 SEQID-03465 P0C074 — — 0 0.40 0.19 0.02 0.140.03 0.05 0.00 0.09 0.083 0.03 0.03 0.05 0.12 0.09 SEQID-03466 P0C0T4 —— 0 0.49 0.21 0.09 0.09 0.00 0.04 0.00 0.05 0.05 0.02 0.03 0.08 0.080.19 SEQID-03467 P0C453 — — 1 0.52 0.11 0.02 0.11 0.03 0.00 0.00 0.060.02 0.02 0.02 0.03 0.03 0.22 SEQID-03468 P0C5N1 — — 1 0.62 0.25 0.020.21 0.03 0.00 0.02 0.00 0.04 0.03 0.15 0.10 0.12 0.04 SEQID-03469P0C5N3 — — 1 0.60 0.23 0.02 0.03 0.05 0.04 0.00 0.04 0.13 0.02 0.01 0.060.14 0.16 SEQID-03470 P10669 — — 1 0.37 0.15 0.03 0.06 0.05 0.05 0.100.04 0.11 0.04 0.01 0.03 0.08 0.09 SEQID-03471 P12902 — — 0 0.36 0.010.12 0.06 0.04 0.07 0.00 0.01 0.18 0.03 0.01 0.00 0.01 0.29 SEQID-03472P13204 — — 1 0.35 0.23 0.04 0.17 0.01 0.05 0.02 0.07 0.08 0.07 0.04 0.020.16 0.01 SEQID-03473 P14402 — — 0 0.06 0.01 0.01 0.72 0.00 0.00 0.000.00 0.00 0.02 0.00 0.00 0.00 0.00 SEQID-03474 P15720 — — 1 0.41 0.100.04 0.16 0.01 0.04 0.00 0.03 0.02 0.09 0.10 0.02 0.04 0.08 SEQID-03475P19114 — — 1 0.56 0.26 0.03 0.04 0.06 0.04 0.02 0.03 0.09 0.01 0.02 0.040.17 0.11 SEQID-03476 P19948 — — 1 0.50 0.25 0.04 0.18 0.05 0.03 0.010.04 0.00 0.02 0.02 0.12 0.10 0.11 SEQID-03477 P20158 — — 0 0.28 0.060.03 0.18 0.07 0.02 0.16 0.10 0.02 0.08 0.00 0.04 0.00 0.10 SEQID-03478P20159 — — 0 0.29 0.10 0.03 0.15 0.04 0.04 0.16 0.10 0.03 0.08 0.00 0.020.02 0.10 SEQID-03479 P23935 — — 0 0.52 0.25 0.04 0.05 0.03 0.02 0.010.06 0.14 0.03 0.02 0.07 0.13 0.13 SEQID-03480 P24052 — — 1 0.49 0.140.07 0.04 0.02 0.04 0.07 0.02 0.08 0.05 0.01 0.02 0.09 0.23 SEQID-03481P25362 — — 1 0.52 0.19 0.04 0.05 0.03 0.07 0.02 0.03 0.10 0.01 0.03 0.040.11 0.09 SEQID-03482 P27007 — — 1 0.45 0.30 0.07 0.10 0.02 0.05 0.000.05 0.11 0.00 0.01 0.03 0.10 0.10 SEQID-03483 P30562 — — 1 0.60 0.210.06 0.04 0.02 0.05 0.00 0.02 0.10 0.04 0.10 0.06 0.12 0.14 SEQID-03484P31162 — — 1 0.62 0.20 0.03 0.09 0.08 0.02 0.00 0.00 0.04 0.04 0.07 0.110.06 0.17 SEQID-03485 P31853 — — 0 0.54 0.26 0.06 0.03 0.02 0.05 0.000.05 0.10 0.01 0.01 0.06 0.16 0.12 SEQID-03486 P32046 — — 1 0.57 0.160.06 0.09 0.01 0.01 0.04 0.03 0.09 0.05 0.03 0.06 0.03 0.20 SEQID-03487P32344 — — 1 0.53 0.15 0.03 0.17 0.04 0.01 0.01 0.04 0.04 0.04 0.01 0.040.07 0.13 SEQID-03488 P32570 — — 1 0.52 0.24 0.04 0.05 0.07 0.06 0.010.07 0.12 0.00 0.01 0.07 0.11 0.07 SEQID-03489 P32760 — — 1 0.50 0.090.03 0.04 0.04 0.03 0.07 0.08 0.08 0.04 0.01 0.01 0.05 0.24 SEQID-03490P33309 — — 1 0.54 0.23 0.03 0.01 0.04 0.09 0.01 0.03 0.09 0.02 0.02 0.070.11 0.16 SEQID-03491 P36047 — — 1 0.52 0.28 0.01 0.03 0.10 0.07 0.000.03 0.10 0.01 0.03 0.08 0.17 0.11 SEQID-03492 P36071 — — 1 0.63 0.230.01 0.09 0.05 0.02 0.00 0.02 0.07 0.00 0.03 0.10 0.10 0.10 SEQID-03493P36493 — — 0 0.60 0.15 0.04 0.12 0.05 0.00 0.00 0.02 0.00 0.02 0.00 0.050.05 0.24 SEQID-03494 P36835 — — 1 0.54 0.25 0.03 0.04 0.06 0.05 0.020.04 0.09 0.01 0.02 0.03 0.18 0.10 SEQID-03495 P37360 — — 0 0.24 0.010.05 0.00 0.00 0.03 0.30 0.02 0.17 0.06 0.00 0.00 0.00 0.15 SEQID-03496P38202 — — 1 0.51 0.13 0.04 0.11 0.02 0.07 0.00 0.05 0.08 0.02 0.03 0.030.07 0.23 SEQID-03497 P38828 — — 1 0.54 0.25 0.01 0.05 0.05 0.05 0.000.08 0.08 0.03 0.01 0.09 0.07 0.14 SEQID-03498 P40060 — — 0 0.45 0.240.02 0.05 0.03 0.10 0.00 0.03 0.14 0.01 0.01 0.08 0.11 0.09 SEQID-03499P40062 — — 0 0.58 0.24 0.02 0.10 0.04 0.03 0.02 0.00 0.04 0.01 0.04 0.050.15 0.13 SEQID-03500 P40509 — — 1 0.48 0.24 0.04 0.01 0.08 0.07 0.010.07 0.10 0.02 0.02 0.05 0.15 0.08 SEQID-03501 P40619 — — 1 0.41 0.070.08 0.04 0.05 0.11 0.00 0.05 0.11 0.03 0.01 0.01 0.02 0.23 SEQID-03502P40620 — — 1 0.40 0.08 0.06 0.03 0.04 0.10 0.01 0.02 0.18 0.04 0.01 0.010.03 0.23 SEQID-03503 P41648 — — 1 0.47 0.28 0.00 0.15 0.03 0.06 0.000.09 0.01 0.03 0.03 0.07 0.18 0.09 SEQID-03504 P43389 — — 0 0.35 0.140.09 0.00 0.05 0.12 0.16 0.02 0.06 0.05 0.00 0.05 0.00 0.12 SEQID-03505P46963 — — 1 0.50 0.19 0.02 0.06 0.05 0.09 0.01 0.05 0.06 0.00 0.04 0.050.11 0.089 SEQID-03506 P46988 — — 1 0.51 0.22 0.03 0.06 0.05 0.06 0.010.03 0.08 0.00 0.01 0.04 0.13 0.14 SEQID-03507 P47005 — — 1 0.50 0.240.02 0.05 0.09 0.07 0.01 0.04 0.06 0.00 0.09 0.09 0.12 0.08 SEQID-03508P47815 — — 1 0.41 0.19 0.03 0.10 0.04 0.13 0.02 0.03 0.10 0.06 0.02 0.060.07 0.13 SEQID-03509 P50291 — — 1 0.37 0.15 0.04 0.07 0.05 0.05 0.100.04 0.10 0.04 0.01 0.03 0.08 0.09 SEQID-03510 P53079 — — 1 0.51 0.250.01 0.04 0.08 0.08 0.01 0.07 0.05 0.00 0.03 0.06 0.15 0.07 SEQID-03511P53335 — — 1 0.53 0.13 0.09 0.08 0.05 0.10 0.00 0.02 0.08 0.03 0.04 0.040.07 0.23 SEQID-03512 P53910 — — 0 0.61 0.26 0.03 0.10 0.03 0.02 0.000.04 0.05 0.02 0.06 0.10 0.08 0.14 SEQID-03513 P53970 — — 1 0.54 0.260.03 0.05 0.03 0.06 0.02 0.03 0.10 0.04 0.03 0.05 0.15 0.11 SEQID-03514P55944 — — 0 0.24 0.01 0.05 0.00 0.00 0.03 0.30 0.02 0.17 0.06 0.00 0.000.00 0.15 SEQID-03515 P60577 — — 1 0.58 0.18 0.03 0.10 0.05 0.01 0.000.00 0.08 0.02 0.08 0.03 0.04 0.12 SEQID-03516 P60750 — — 1 0.53 0.170.06 0.01 0.03 0.07 0.00 0.08 0.05 0.03 0.02 0.05 0.07 0.18 SEQID-03517P61848 — — 0 0.60 0.14 0.02 0.10 0.04 0.00 0.00 0.04 0.00 0.03 0.00 0.060.06 0.25 SEQID-03518 P68080 — — 1 0.58 0.21 0.06 0.04 0.02 0.05 0.000.02 0.10 0.04 0.10 0.05 0.12 0.14 SEQID-03519 P71479 — — 0 0.49 0.290.06 0.11 0.03 0.10 0.00 0.04 0.07 0.04 0.05 0.09 0.11 0.05 SEQID-03520P80272 — — 0 0.36 0.03 0.12 0.07 0.04 0.10 0.00 0.04 0.08 0.06 0.00 0.000.01 0.30 SEQID-03521 P80680 — — 1 0.46 0.21 0.08 0.10 0.01 0.06 0.010.04 0.12 0.03 0.03 0.02 0.05 0.08 SEQID-03522 P81558 — — 1 0.38 0.090.06 0.15 0.01 0.06 0.00 0.06 0.01 0.03 0.07 0.02 0.06 0.09 SEQID-03523P82010 — — 0 0.33 0.04 0.04 0.09 0.07 0.04 0.16 0.05 0.05 0.03 0.00 0.000.02 0.10 SEQID-03524 P82920 — — 1 0.39 0.14 0.03 0.22 0.05 0.03 0.090.04 0.08 0.02 0.01 0.06 0.05 0.07 SEQID-03525 P83487 — — 1 0.39 0.110.04 0.17 0.01 0.06 0.00 0.05 0.01 0.08 0.07 0.02 0.06 0.08 SEQID-03526PB49

7 — — 1 0.59 0.20 0.07 0.02 0.03 0.05 0.00 0.03 0.11 0.04 0.10 0.04 0.110.13 SEQID-03527 Q02368 — — 1 0.37 0.13 0.05 0.16 0.01 0.07 0.03 0.050.11 0.02 0.04 0.01 0.09 0.07 SEQID-03528 Q034H8 — — 1 0.53 0.28 0.050.06 0.03 0.07 0.00 0.05 0.09 0.05 0.05 0.08 0.13 0.09 SEQID-03529Q034Z7 — — 1 0.49 0.28 0.04 0.11 0.05 0.07 0.00 0.01 0.07 0.04 0.01 0.110.08 0.11 SEQID-03530 Q03525 — — 1 0.50 0.11 0.03 0.03 0.04 0.07 0.000.01 0.09 0.04 0.03 0.02 0.05 0.27 SEQID-03531 Q038I0 — — 1 0.56 0.200.05 0.18 0.05 0.03 0.00 0.02 0.00 0.03 0.06 0.05 0.08 0.15 SEQID-03532Q03919 — — 0 0.58 0.31 0.01 0.04 0.01 0.05 0.00 0.07 0.12 0.04 0.05 0.080.16 0.12 SEQID-03533 Q03AJ7 — — 1 0.46 0.20 0.05 0.14 0.07 0.05 0.000.04 0.07 0.03 0.04 0.04 0.11 0.13 SEQID-03534 Q03AZ68 — — 1 0.37 0.170.04 0.00 0.06 0.17 0.00 0.05 0.14 0.02 0.01 0.04 0.09 0.03 SEQID-03535Q042Y3 — — 1 0.54 0.28 0.03 0.06 0.04 0.08 0.01 0.04 0.03 0.03 0.02 0.080.14 0.12 SEQID-03536 Q043Y6 — — 0 0.52 0.29 0.04 0.04 0.07 0.06 0.000.07 0.07 0.03 0.02 0.07 0.14 0.11 SEQID-03537 Q045P3 — — 1 0.37 0.190.03 0.03 0.06 0.19 0.00 0.05 0.11 0.02 0.01 0.04 0.09 0.02 SEQID-03538Q046A4 — — 0 0.54 0.27 0.03 0.09 0.03 0.06 0.00 0.00 0.09 0.03 0.03 0.100.08 0.09 SEQID-03539 Q04869 — — 1 0.51 0.23 0.06 0.03 0.05 0.07 0.010.04 0.07 0.04 0.03 0.06 0.08 0.11 SEQID-03540 Q048Z6 — — 1 0.37 0.190.05 0.03 0.03 0.20 0.00 0.04 0.15 0.02 0.02 0.04 0.09 0.01 SEQID-03541Q04935 — — 1 0.47 0.14 0.04 0.05 0.04 0.05 0.01 0.11 0.06 0.02 0.02 0.040.08 0.11 SEQID-03542 Q049N0 — — 1 0.49 0.29 0.06 0.06 0.03 0.08 0.010.03 0.08 0.04 0.03 0.08 0.11 0.10 SEQID-03543 Q04C52 — — 1 0.34 0.140.03 0.06 0.05 0.25 0.00 0.03 0.14 0.02 0.03 0.04 0.06 0.04 SEQID-03544Q05462 — — 1 0.62 0.21 0.04 0.07 0.02 0.06 0.01 0.02 0.09 0.02 0.02 0.030.09 0.23 SEQID-03545 Q05566 — — 1 0.50 0.09 0.03 0.11 0.05 0.00 0.000.06 0.02 0.02 0.02 0.03 0.03 0.22 SEQID-03546 Q06071 — — 1 0.49 0.230.01 0.03 0.08 0.05 0.01 0.04 0.10 0.00 0.03 0.07 0.12 0.10 SEQID-03547Q06162 — — 1 0.43 0.26 0.03 0.07 0.04 0.05 0.00 0.12 0.11 0.01 0.02 0.070.18 0.03 SEQID-03548 Q06835 — — 1 0.44 0.19 0.01 0.10 0.07 0.07 0.110.04 0.04 0.04 0.02 0.05 0.08 0.14 SEQID-03549 Q06891 — — 1 0.44 0.260.02 0.12 0.03 0.08 0.03 0.06 0.06 0.00 0.01 0.07 0.15 0.04 SEQID-03550Q08273 — — 1 0.44 0.14 0.06 0.07 0.07 0.08 0.07 0.06 0.07 0.01 0.04 0.060.02 0.07 SEQID-03551 Q08423 — — 0 0.48 0.16 0.01 0.36 0.01 0.01 0.000.02 0.00 0.00 0.24 0.01 0.13 0.03 SEQID-03552 Q09MB5 — — 0 0.56 0.250.00 0.06 0.06 0.02 0.00 0.05 0.12 0.01 0.05 0.04 0.21 0.07 SEQID-03553Q09ME2 — — 1 0.47 0.27 0.03 0.20 0.07 0.04 0.01 0.00 0.06 0.04 0.01 0.140.09 0.07 SEQID-03554 Q09MF5 — — 1 0.43 0.24 0.04 0.25 0.06 0.02 0.010.04 0.01 0.01 0.02 0.11 0.09 0.06 SEQID-03555 Q0II65 — — 1 0.50 0.130.04 0.12 0.02 0.03 0.00 0.02 0.20 0.02 0.02 0.02 0.07 0.11 SEQID-03556Q0P5B3 — — 1 0.44 0.18 0.04 0.08 0.05 0.08 0.09 0.06 0.04 0.04 0.02 0.030.11 0.09 SEQID-03557 Q0VCD4 — — 1 0.50 0.23 0.04 0.10 0.04 0.06 0.010.03 0.08 0.03 0.05 0.04 0.12 0.04 SEQID-03558 Q0VD26 — — 1 0.44 0.140.03 0.11 0.06 0.04 0.01 0.03 0.10 0.08 0.03 0.01 0.08 0.06 SEQID-03559Q12028 — — 1 0.51 0.28 0.03 0.04 0.07 0.03 0.01 0.04 0.07 0.02 0.02 0.090.15 0.09 SEQID-03560 Q14FD4 — — 1 0.43 0.23 0.05 0.24 0.07 0.02 0.010.04 0.01 0.01 0.02 0.10 0.11 0.05 SEQID-03561 Q17Q91 — — 1 0.37 0.120.03 0.13 0.07 0.06 0.04 0.03 0.07 0.02 0.01 0.02 0.06 0.08 SEQID-03562Q1G940 — — 0 0.46 0.24 0.06 0.04 0.04 0.05 0.00 0.04 0.10 0.05 0.00 0.060.10 0.11 SEQID-03563 Q1G9J5 — — 1 0.61 0.18 0.02 0.11 0.07 0.02 0.000.02 0.00 0.03 0.02 0.02 0.07 0.19 SEQID-03564 Q1GBQ3 — — 1 0.33 0.140.04 0.06 0.05 0.25 0.00 0.03 0.14 0.02 0.03 0.04 0.06 0.04 SEQID-03565Q2KI95 — — 1 0.40 0.12 0.03 0.03 0.01 0.06 0.11 0.05 0.08 0.03 0.04 0.040.06 0.09 SEQID-03566 Q2KIA3 — — 1 0.44 0.19 0.04 0.08 0.05 0.07 0.090.04 0.05 0.03 0.02 0.03 0.12 0.10 SEQID-03567 Q2K1T5 — — 1 0.34 0.130.04 0.06 0.03 0.07 0.10 0.05 0.13 0.05 0.01 0.01 0.08 0.05 SEQID-03568Q2L927 — — 1 0.44 0.23 0.04 0.26 0.05 0.02 0.01 0.04 0.01 0.02 0.03 0.110.09 0.08 SEQID-03569 Q2M2S7 — — 1 0.38 0.11 0.05 0.10 0.06 0.05 0.080.04 0.08 0.03 0.04 0.01 0.05 0.06 SEQID-03570 Q2MI60 — — 1 0.59 0.210.04 0.09 0.07 0.03 0.00 0.00 0.05 0.03 0.08 0.11 0.08 0.12 SEQID-03571Q2MJS5 — — 0 0.24 0.01 0.05 0.00 0.00 0.05 0.28 0.02 0.15 0.05 0.00 0.000.00 0.15 SEQID-03572 Q2T9Q2 — — 1 0.44 0.25 0.09 0.11 0.01 0.04 0.010.08 0.13 0.02 0.04 0.02 0.17 0.07 SEQID-03573 Q2TBR9 — — 0 0.55 0.150.04 0.11 0.02 0.06 0.01 0.06 0.07 0.02 0.02 0.04 0.07 0.24 SEQID-03574Q2YDK0 — — 1 0.44 0.12 0.02 0.05 0.03 0.04 0.11 0.02 0.09 0.03 0.05 0.040.05 0.11 SEQID-03575 Q32L75 — — 1 0.50 0.17 0.04 0.10 0.04 0.01 0.010.12 0.10 0.01 0.07 0.02 0.12 0.08 SEQID-03576 Q32PJ6 — — 1 0.42 0.180.05 0.07 0.03 0.03 0.05 0.04 0.09 0.03 0.04 0.02 0.08 0.04 SEQID-03577Q332T6 — — 1 0.57 0.22 0.04 0.10 0.09 0.02 0.00 0.00 0.05 0.03 0.07 0.120.08 0.12 SEQID-03578 Q332U3 — — 0 0.37 0.19 0.02 0.35 0.03 0.00 0.070.06 0.03 0.03 0.03 0.13 0.03 0.11 SEQID-03579 Q3E731 — — 1 0.37 0.130.03 0.07 0.07 0.09 0.04 0.05 0.07 0.04 0.04 0.01 0.11 0.07 SEQID-03580Q3E732 — — 0 0.55 0.24 0.03 0.10 0.05 0.05 0.00 0.00 0.00 0.00 0.00 0.080.10 0.14 SEQID-03581 Q3E747 — — 0 0.60 0.19 0.03 0.10 0.02 0.01 0.000.05 0.07 0.02 0.03 0.00 0.15 0.30 SEQID-03582 Q3E794 — — 0 0.54 0.230.02 0.18 0.04 0.06 0.00 0.02 0.00 0.00 0.09 0.11 0.09 0.06 SEQID-03583Q3E813 — — 0 0.42 0.15 0.02 0.23 0.04 0.02 0.05 0.02 0.06 0.04 0.02 0.020.13 0.00 SEQID-03584 Q3E843 — — 0 0.53 0.19 0.01 0.03 0.02 0.09 0.020.02 0.07 0.01 0.03 0.04 0.13 0.07 SEQID-03585 Q3SZ70 — — 0 0.25 0.080.07 0.20 0.02 0.03 0.04 0.03 0.14 0.06 0.05 0.01 0.05 0.00 SEQID-03586Q3T0Q6 — — 1 0.30 0.08 0.04 0.13 0.03 0.06 0.12 0.03 0.10 0.07 0.06 0.030.03 0.06 SEQID-03587 Q3T0V7 — — 0 0.46 0.19 0.07 0.10 0.03 0.06 0.000.09 0.09 0.04 0.03 0.07 0.07 0.16 SEQID-03588 Q3T0Z3 — — 1 0.56 0.240.02 0.05 0.05 0.09 0.02 0.03 0.05 0.03 0.03 0.08 0.08 0.13 SEQID-03589Q3T0ZB — — 1 0.45 0.23 0.01 0.05 0.07 0.04 0.01 0.01 0.15 0.06 0.01 0.030.13 0.07 SEQID-03590 Q3V4Z3 — — 1 0.58 0.21 0.03 0.10 0.06 0.02 0.000.00 0.09 0.03 0.08 0.11 0.07 0.11 SEQID-03591 Q3ZBK6 — — 1 0.42 0.180.02 0.13 0.04 0.04 0.02 0.08 0.07 0.09 0.02 0.06 0.07 0.09 SEQID-03592Q48585 — — 1 0.52 0.19 0.04 0.07 0.05 0.02 0.00 0.04 0.08 0.02 0.03 0.040.09 0.19 SEQID-03593 Q4VZK1 — — 0 0.39 0.19 0.02 0.34 0.02 0.00 0.070.06 0.03 0.01 0.03 0.15 0.02 0.11 SEQID-03594 Q58CS7 — — 1 0.46 0.200.07 0.03 0.01 0.05 0.00 0.05 0.17 0.02 0.01 0.05 0.09 0.12 SEQID-03595Q58DW3 — — 1 0.47 0.11 0.11 0.13 0.05 0.01 0.01 0.04 0.03 0.03 0.04 0.030.06 0.22 SEQID-03596 Q56IS3 — — 1 0.46 0.13 0.02 0.14 0.04 0.04 0.020.04 0.07 0.06 0.05 0.04 0.05 0.09 SEQID-03597 Q5E9Z8 — — 0 0.48 0.290.02 0.09 0.02 0.07 0.00 0.07 0.13 0.03 0.03 0.08 0.13 0.08 SEQID-03598Q5EA80 — — 1 0.44 0.24 0.04 0.09 0.04 0.05 0.03 0.07 0.10 0.02 0.03 0.020.18 0.04 SEQID-03599 Q5F4C4 — — 1 0.51 0.27 0.02 0.06 0.09 0.04 0.010.03 0.09 0.03 0.02 0.05 0.18 0.10 SEQID-03600 Q5FHT1 — — 1 0.52 0.200.04 0.01 0.06 0.08 0.01 0.04 0.08 0.03 0.03 0.10 0.06 0.13 SEQID-03601Q5FJI3 — — 1 0.58 0.18 0.09 0.13 0.05 0.03 0.00 0.02 0.00 0.03 0.02 0.020.06 0.20 SEQID-03602 Q5FK48 — — 1 0.51 0.23 0.03 0.08 0.03 0.08 0.020.01 0.10 0.04 0.05 0.08 0.10 0.07 SEQID-03603 Q5FKL2 — — 0 0.53 0.290.03 0.03 0.06 0.06 0.00 0.07 0.09 0.03 0.02 0.08 0.14 0.12 SEQID-03604Q5FLW3 — — 1 0.37 0.19 0.04 0.03 0.05 0.21 0.00 0.06 0.09 0.03 0.02 0.040.09 0.02 SEQID-03605 Q5FM69 — — 0 0.54 0.27 0.03 0.09 0.03 0.07 0.000.00 0.08 0.03 0.03 0.10 0.08 0.09 SEQID-03606 Q5FM79 — — 0 0.60 0.240.03 0.02 0.08 0.04 0.00 0.03 0.06 0.06 0.03 0.05 0.01 0.25 SEQID-03607Q5FME7 — — 1 0.32 0.14 0.04 0.05 0.06 0.24 0.00 0.02 0.12 0.02 0.02 0.040.06 0.05 SEQID-03608 Q5QHW1 — — 1 0.51 0.22 0.04 0.06 0.03 0.07 0.020.01 0.10 0.04 0.05 0.06 0.10 0.09 SEQID-03609 Q5ZHK9 — — 0 0.53 0.160.05 0.12 0.03 0.05 0.01 0.05 0.08 0.02 0.01 0.02 0.10 0.24 SEQID-03610Q5ZI72 — — 1 0.35 0.11 0.03 0.06 0.05 0.06 0.01 0.08 0.08 0.09 0.01 0.030.04 0.10 SEQID-03611 Q5ZIR5 — — 0 0.37 0.03 0.08 0.07 0.04 0.03 0.000.04 0.17 0.04 0.00 0.00 0.01 0.26 SEQID-03612 Q5Z

6 — — 1 0.45 0.23 0.05 0.10 0.02 0.05 0.02 0.07 0.08 0.03 0.08 0.04 0.120.07 SEQID-03613 Q5ZK61 — — 1 0.45 0.15 0.02 0.16 0.01 0.04 0.02 0.040.07 0.06 0.05 0.04 0.05 0.07 SEQID-03614 Q6PVZ5 — — 1 0.38 0.19 0.050.10 0.04 0.04 0.00 0.05 0.09 0.10 0.01 0.04 0.10 0.06 SEQID-03615Q6Q311 — — 1 0.51 0.19 0.07 0.07 0.04 0.08 0.01 0.02 0.04 0.04 0.01 0.030.10 0.25 SEQID-03616 Q6Q546 — — 0 0.53 0.31 0.01 0.04 0.04 0.08 0.010.06 0.08 0.03 0.03 0.05 0.14 0.12 SEQID-03617 Q6XXM1 — — 1 0.31 0.190.07 0.27 0.00 0.02 0.01 0.06 0.05 0.02 0.02 0.01 0.14 0.02 SEQID-03618Q74IM0 — — 1 0.52 0.28 0.05 0.05 0.05 0.07 0.00 0.03 0.08 0.04 0.02 0.100.10 0.11 SEQID-03619 Q74IV9 — — 0 0.52 0.29 0.05 0.04 0.07 0.06 0.000.07 0.07 0.03 0.02 0.07 0.14 0.11 SEQID-03620 Q74I20 — — 1 0.54 0.280.04 0.06 0.04 0.08 0.01 0.04 0.03 0.03 0.02 0.08 0.14 0.12 SEQID-03621Q74LG3 — — 1 0.35 0.16 0.03 0.05 0.05 0.23 0.00 0.04 0.13 0.02 0.03 0.050.07 0.04 SEQID-03622 Q7Y1H8 — — 1 0.35 0.14 0.10 0.11 0.01 0.09 0.020.02 0.05 0.08 0.01 0.02 0.07 0.08 SEQID-03623 Q85WU8 — — 1 0.49 0.290.00 0.16 0.02 0.06 0.00 0.09 0.01 0.02 0.03 0.07 0.18 0.09 SEQID-03624Q88V14 — — 1 0.39 0.20 0.04 0.01 0.07 0.19 0.00 0.07 0.10 0.03 0.01 0.060.09 0.01 SEQID-03625 Q88V75 — — 1 0.47 0.18 0.08 0.10 0.01 0.07 0.020.06 0.10 0.03 0.02 0.06 0.09 0.05 SEQID-03626 Q88WJ7 — — 0 0.41 0.210.04 0.05 0.06 0.07 0.00 0.07 0.12 0.01 0.04 0.08 0.09 0.07 SEQID-03627Q88WK6 — — 1 0.57 0.18 0.04 0.16 0.05 0.03 0.00 0.02 0.00 0.03 0.06 0.020.06 0.16 SEQID-03628 Q28X0S — — 1 0.54 0.19 0.04 0.01 0.06 0.06 0.000.05 0.03 0.03 0.01 0.04 0.10 0.18 SEQID-03629 Q88XW8 — — 0 0.56 0.310.06 0.13 0.02 0.05 0.00 0.06 0.04 0.03 0.06 0.12 0.10 0.12 SEQID-03630Q88Z77 — — 1 0.33 0.16 0.04 0.03 0.03 0.28 0.00 0.04 0.10 0.03 0.02 0.050.08 0.05 SEQID-03631 Q8H7U1 — — 1 0.43 0.17 0.04 0.07 0.05 0.07 0.020.05 0.09 0.04 0.03 0.03 0.08 0.04 SEQID-03632 Q83HZ03 — — 1 0.45 0.260.05 0.10 0.03 0.05 0.05 0.06 0.08 0.04 0.02 0.06 0.18 0.07 SEQID-03633Q8LJS2 — — 1 0.42 0.14 0.05 0.01 0.03 0.12 0.01 0.04 0.11 0.04 0.03 0.030.06 0.15 SEQID-03634 Q8SPJ1 — — 1 0.45 0.24 0.06 0.07 0.05 0.05 0.020.06 0.07 0.03 0.03 0.05 0.13 0.05 SEQID-03635 Q8TGQ6 — — 0 0.40 0.080.06 0.17 0.06 0.06 0.09 0.00 0.02 0.02 0.02 0.00 0.04 0.09 SEQID-03636Q3TGU5 — — 1 0.65 0.24 0.02 0.07 0.05 0.05 0.00 0.00 0.00 0.03 0.09 0.050.10 0.14 SEQID-03637 Q90370 — — 1 0.43 0.13 0.03 0.08 0.03 0.04 0.010.09 0.08 0.02 0.12 0.02 0.08 0.05 SEQID-03638 Q90886 — — 1 0.42 0.130.03 0.08 0.03 0.04 0.01 0.09 0.08 0.02 0.12 0.02 0.08 0.05 SEQID-03639Q9SKV7 — — 1 0.47 0.19 0.04 0.12 0.02 0.03 0.00 0.03 0.09 0.04 0.01 0.030.10 0.05 SEQID-03640 Q9M4U5 — — 1 0.42 0.12 0.05 0.00 0.03 0.13 0.010.03 0.13 0.04 0.03 0.02 0.06 0.16 SEQID-03641 WSP481 — — 1 0.24 0.100.07 0.08 0.02 0.05 0.01 0.05 0.06 0.15 0.01 0.02 0.04 0.05 SEQID-03642WSPVF9 — — 1 0.37 0.15 0.04 0.09 0.05 0.06 0.02 0.05 0.08 0.03 0.04 0.030.07 0.06 SEQID-03643 A1A080 — — 0 0.51 0.26 0.05 0.13 0.01 0.06 0.000.07 0.08 0.04 0.02 0.07 0.04 0.17 SEQID-03644 A1A092 — — 0 0.42 0.210.00 0.25 0.05 0.00 0.07 0.06 0.08 0.03 0.06 0.08 0.00 0.09 SEQID-03645A1A093 — — 0 0.43 0.20 0.05 0.19 0.04 0.06 0.01 0.04 0.06 0.04 0.01 0.100.07 0.12 SEQID-03646 A1A1E3 — — 0 0.46 0.19 0.18 0.09 0.08 0.03 0.000.04 0.04 0.03 0.03 0.05 0.06 0.19 SEQID-03647 A1A2C3 — — 0 0.51 0.140.07 0.15 0.05 0.02 0.00 0.02 0.04 0.04 0.06 0.00 0.10 0.18 SEQID-03648A1A4Q4 — — 0 0.52 0.08 0.06 0.02 0.00 0.03 0.00 0.09 0.15 0.06 0.00 0.020.06 0.36 SEQID-03649 A2QCV8 — — 1 0.49 0.19 0.04 0.02 0.06 0.08 0.030.03 0.04 0.07 0.02 0.08 0.05 0.10 SEQID-03650 A2QEJ9 — — 1 0.44 0.180.05 0.05 0.07 0.08 0.02 0.02 0.05 0.04 0.02 0.05 0.08 0.06 SEQID-03651A2WNH1 — — 0 0.46 0.17 0.03 0.05 0.02 0.01 0.14 0.05 0.05 0.07 0.08 0.070.05 0.08 SEQID-03652 A2Y1D7 — — 0 0.38 0.09 0.04 0.00 0.03 0.08 0.150.02 0.11 0.07 0.04 0.02 0.00 0.15 SEQID-03653 A2Y720 — — 0 0.39 0.050.16 0.04 0.01 0.08 0.00 0.09 0.11 0.05 0.03 0.01 0.02 0.16 SEQID-03654A3B0Y1 — — 0 0.36 0.09 0.04 0.00 0.05 0.08 0.15 0.02 0.11 0.07 0.02 0.020.00 0.15 SEQID-03655 A4GG84 — — 1 0.54 0.25 0.03 0.08 0.05 0.02 0.010.07 0.07 0.04 0.02 0.15 0.05 0.13 SEQID-03656 A4GGE4 — — 0 0.61 0.140.05 0.08 0.06 0.00 0.02 0.02 0.00 0.02 0.00 0.06 0.07 0.23 SEQID-03657A4GGF3 — — 0 0.50 0.22 0.00 0.12 0.04 0.03 0.00 0.11 0.04 0.03 0.03 0.080.11 0.13 SEQID-03658 A5D962 — — 1 0.35 0.12 0.05 0.10 0.01 0.07 0.020.03 0.11 0.04 0.01 0.03 0.07 0.09 SEQID-03659 A5VJC3 — — 0 0.46 0.140.03 0.11 0.04 0.04 0.02 0.04 0.07 0.01 0.07 0.02 0.09 0.12 SEQID-03660A5VKX3 — — 0 0.55 0.07 0.04 0.16 0.06 0.02 0.00 0.03 0.00 0.04 0.04 0.000.06 0.22 SEQID-03661 A5VLI2 — — 0 0.53 0.16 0.02 0.14 0.05 0.00 0.070.06 0.03 0.03 0.06 0.05 0.00 0.23 SEQID-03662 A5VLK1 — — 1 0.56 0.150.03 0.08 0.00 0.06 0.00 0.02 0.06 0.05 0.05 0.03 0.04 0.16 SEQID-03663A6QQ14 — — 0 0.35 0.18 0.15 0.10 0.01 0.08 0.02 0.05 0.10 0.04 0.00 0.040.10 0.05 SEQID-03664 A6QQ66 — — 0 0.34 0.12 0.03 0.01 0.06 0.13 0.020.02 0.25 0.01 0.03 0.03 0.08 0.07 SEQID-03665 A7Y3K4 — — 0 0.56 0.240.01 0.10 0.05 0.02 0.00 0.06 0.08 0.02 0.04 0.07 0.13 0.18 SEQID-03666B0JEU3 — — 1 0.35 0.16 0.03 0.12 0.06 0.04 0.02 0.13 0.11 0.04 0.02 0.040.07 0.06 SEQID-03667 B1A991 — — 0 0.50 0.22 0.00 0.14 0.06 0.02 0.000.06 0.07 0.02 0.02 0.07 0.12 0.15 SEQID-03668 B2G5T7 — — 0 0.49 0.240.14 0.00 0.02 0.13 0.00 0.00 0.11 0.04 0.00 0.07 0.08 0.16 SEQID-03669B2G6N9 — — 0 0.44 0.16 0.05 0.04 0.07 0.06 0.00 0.06 0.14 0.00 0.02 0.030.08 0.09 SEQID-03670 B2G7V3 — — 0 0.48 0.15 0.06 0.15 0.02 0.03 0.000.02 0.05 0.03 0.07 0.04 0.089 0.18 SEQID-03671 B2G8D6 — — 0 0.43 0.160.04 0.03 0.05 0.08 0.00 0.17 0.08 0.02 0.01 0.04 0.07 0.10 SEQID-03672B3Y1Y0 — — 0 0.62 0.14 0.02 0.08 0.03 0.00 0.05 0.03 0.05 0.02 0.07 0.030.06 0.21 SEQID-03673 B3Y208 — — 0 0.51 0.20 0.00 0.13 0.07 0.04 0.010.09 0.00 0.02 0.03 0.05 0.12 0.15 SEQID-03674 B3DQC5 — — 0 0.51 0.250.05 0.12 0.02 0.05 0.00 0.07 0.07 0.05 0.02 0.07 0.04 0.16 SEQID-03675B3DQT3 — — 0 0.53 0.15 0.07 0.13 0.03 0.03 0.00 0.05 0.04 0.04 0.08 0.020.10 0.20 SEQID-03676 B3DRN7 — — 0 0.29 0.13 0.11 0.00 0.03 0.13 0.000.19 0.14 0.02 0.00 0.03 0.06 0.02 SEQID-03677 B30S06 — — 1 0.53 0.190.05 0.03 0.00 0.05 0.00 0.04 0.17 0.03 0.06 0.05 0.10 0.09 SEQID-03678B3DSB0 — — 0 0.46 0.21 0.18 0.09 0.08 0.03 0.00 0.04 0.04 0.03 0.03 0.060.08 0.17 SEQID-03679 B3LMP9 — — 1 0.48 0.20 0.02 0.09 0.06 0.089 0.000.04 0.04 0.04 0.02 0.05 0.06 0.07 SEQID-03680 B3W9Z1 — — 0 0.49 0.140.04 0.03 0.02 0.09 0.00 0.11 0.09 0.04 0.00 0.07 0.04 0.13 SEQID-03681B3WF72 — — 0 0.46 0.18 0.04 0.01 0.03 0.10 0.00 0.18 0.06 0.02 0.00 0.060.09 0.11 SEQID-03682 B7GRY8 — — 0 0.44 0.21 0.18 0.10 0.08 0.03 0.000.04 0.04 0.03 0.03 0.06 0.08 0.16 SEQID-03683 B7GUP0 — — 0 0.33 0.150.08 0.00 0.03 0.13 0.00 0.19 0.14 0.02 0.00 0.03 0.06 0.02 SEQID-03684B8DSI4 — — 0 0.40 0.25 0.09 0.07 0.02 0.08 0.00 0.04 0.15 0.02 0.01 0.060.10 0.00 SEQID-03685 B8DSQ1 — — 0 0.57 0.14 0.09 0.16 0.02 0.03 0.000.04 0.02 0.04 0.06 0.00 0.10 0.20 SEQID-03686 B8DUL7 — — 0 0.41 0.170.15 0.14 0.07 0.02 0.00 0.07 0.04 0.02 0.01 0.07 0.05 0.15 SEQID-03687B8DV05 — — 0 0.37 0.08 0.05 0.38 0.06 0.00 0.00 0.02 0.00 0.03 0.03 0.020.04 0.10 SEQID-03688 B8DW24 — — 0 0.53 0.27 0.04 0.13 0.01 0.06 0.000.06 0.07 0.05 0.02 0.07 0.04 0.17 SEQID-03689 D5DEH5 — — 1 0.41 0.170.06 0.03 0.07 0.07 0.00 0.04 0.04 0.05 0.02 0.04 0.06 0.09 SEQID-03690E1UMM6 — — 1 0.43 0.17 0.04 0.04 0.08 0.06 0.01 0.02 0.04 0.06 0.01 0.060.08 0.07 SEQID-03691 E1UQB7 — — 1 0.52 0.16 0.05 0.01 0.03 0.10 0.000.05 0.09 0.03 0.01 0.03 0.08 0.23 SEQID-03692 E1UV85 — — 0 0.44 0.200.07 0.01 0.06 0.05 0.00 0.14 0.07 0.04 0.00 0.05 0.06 0.13 SEQID-03693E7Q903 — — 1 0.34 0.09 0.03 0.07 0.10 0.08 0.00 0.10 0.06 0.05 0.01 0.030.04 0.098 SEQID-03694 I1LP26 — — 1 0.49 0.17 0.03 0.05 0.05 0.08 0.010.04 0.07 0.02 0.03 0.05 0.07 0.17 SEQID-03695 K1WSX8 — — 1 0.38 0.140.07 0.10 0.02 0.04 0.00 0.17 0.10 0.01 0.02 0.02 0.07 0.07 SEQID-03696K7K247 — — 1 0.48 0.12 0.04 0.04 0.05 0.04 0.01 0.07 0.15 0.01 0.03 0.030.07 0.19 SEQID-03697 O13555 — — 0 0.42 0.23 0.09 0.05 0.04 0.16 0.020.00 0.25 0.00 0.01 0.03 0.13 0.07 SEQID-03693 O49224 — — 0 0.47 0.070.00 0.40 0.00 0.00 0.00 0.04 0.00 0.05 0.00 0.00 0.04 0.25 SEQID-03699P00126 — — 0 0.37 0.17 0.02 0.10 0.01 0.08 0.05 0.05 0.24 0.02 0.04 0.000.13 0.06 SEQID-03700 P00227 — — 0 0.37 0.19 0.06 0.02 0.00 0.12 0.050.04 0.15 0.03 0.01 0.04 0.05 0.05 SEQID-03701 P01249 — — 0 0.49 0.270.04 0.06 0.04 0.04 0.00 0.07 0.12 0.02 0.02 0.00 0.18 0.11 SEQID-03702P01250 — — 0 0.47 0.27 0.04 0.06 0.04 0.04 0.00 0.05 0.14 0.01 0.00 0.000.18 0.11 SEQID-03703 P01251 — — 0 0.49 0.27 0.04 0.06 0.04 0.02 0.000.05 0.16 0.01 0.02 0.00 0.18 0.11 SEQID-03704 P02318 — — 0 0.17 0.060.01 0.60 0.00 0.00 0.11 0.02 0.00 0.02 0.02 0.02 0.02 0.00 SEQID-03705P02405 — — 0 0.56 0.12 0.09 0.10 0.01 0.01 0.04 0.09 0.03 0.04 0.04 0.000.06 0.24 SEQID-03706 P02633 — — 0 0.49 0.21 0.02 0.00 0.03 0.05 0.000.06 0.19 0.03 0.00 0.03 0.15 0.16 SEQID-03707 P02777 — — 0 0.45 0.220.03 0.05 0.01 0.07 0.04 0.05 0.08 0.04 0.03 0.06 0.13 0.11 SEQID-03708P04464 — — 0 0.45 0.17 0.09 0.04 0.02 0.01 0.13 0.05 0.05 0.07 0.08 0.070.05 0.08 SEQID-03709 P04568 — — 0 0.27 0.09 0.04 0.16 0.02 0.06 0.000.09 0.16 0.10 0.00 0.02 0.05 0.08 SEQID-03710 P04650 — — 0 0.46 0.110.06 0.22 0.11 0.00 0.00 0.08 0.00 0.00 0.00 0.07 0.04 0.16 SEQID-03711P05747 — — 0 0.56 0.08 0.10 0.09 0.07 0.02 0.00 0.02 0.00 0.03 0.12 0.020.05 0.25 SEQID-03712 P05936 — — 0 0.46 0.18 0.04 0.04 0.02 0.00 0.130.03 0.06 0.08 0.09 0.08 0.03 0.07 SEQID-03713 P07249 — — 0 0.42 0.160.03 0.09 0.04 0.09 0.01 0.03 0.09 0.02 0.01 0.06 0.06 0.08 SEQID-03714P07269 — — 1 0.40 0.16 0.03 0.06 0.14 0.10 0.00 0.07 0.05 0.01 0.04 0.060.08 0.05 SEQID-03715 P09441 — — 0 0.29 0.04 0.07 0.11 0.06 0.09 0.000.06 0.08 0.10 0.03 0.01 0.01 0.07 SEQID-03716 P0C225 — — 0 0.26 0.160.06 0.08 0.02 0.10 0.04 0.02 0.12 0.04 0.02 0.04 0.10 0.02 SEQID-03717P0C5A4 — — 0 0.38 0.05 0.16 0.04 0.01 0.08 0.00 0.09 0.11 0.04 0.03 0.010.02 0.16 SEQID-03718 P0C5Q9 — — 0 0.42 0.09 0.07 0.12 0.06 0.00 0.000.07 0.07 0.03 0.00 0.03 0.06 0.10 SEQID-03719 P0CSR4 — — 1 0.56 0.250.01 0.11 0.04 0.06 0.02 0.05 0.02 0.01 0.05 0.10 0.08 0.07 SEQID-03720P0CG92 — — 0 0.29 0.13 0.11 0.00 0.03 0.13 0.00 0.19 0.14 0.02 0.00 0.030.06 0.02 SEQID-03721 P10961 — — 1 0.39 0.15 0.03 0.07 0.15 0.08 0.000.04 0.06 0.02 0.03 0.05 0.07 0.06 SEQID-03722 P12230 — — 0 0.40 0.230.02 0.28 0.03 0.00 0.07 0.06 0.03 0.03 0.03 0.15 0.03 0.12 SEQID-03723P14164 — — 1 0.39 0.16 0.03 0.04 0.15 0.12 0.00 0.04 0.07 0.02 0.07 0.050.06 0.08 SEQID-03724 P14724 — — 0 0.38 0.15 0.03 0.04 0.14 0.14 0.000.06 0.06 0.01 0.06 0.05 0.08 0.05 SEQID-03725 P14936 — — 0 0.39 0.190.05 0.01 0.01 0.11 0.04 0.06 0.12 0.04 0.05 0.04 0.07 0.07 SEQID-03726P14937 — — 0 0.41 0.19 0.05 0.01 0.01 0.09 0.05 0.07 0.14 0.04 0.04 0.040.06 0.06 SEQID-03727 P15341 — — 0 0.10 0.06 0.01 0.63 0.00 0.00 0.110.06 0.00 0.00 0.00 0.00 0.02 0.00 SEQID-03728 P17639 — — 0 0.34 0.100.04 0.11 0.02 0.05 0.00 0.10 0.16 0.10 0.03 0.02 0.06 0.12 SEQID-03729P17803 — — 0 0.50 0.19 0.02 0.06 0.05 0.05 0.02 0.09 0.05 0.02 0.00 0.080.08 0.11 SEQID-03730 P19515 — — 1 0.45 0.22 0.04 0.05 0.04 0.06 0.020.03 0.06 0.04 0.03 0.07 0.08 0.03 SEQID-03731 P19757 — — 0 0.16 0.060.01 0.48 0.01 0.03 0.04 0.08 0.05 0.02 0.07 0.01 0.02 0.00 SEQID-03732P19782 — — 0 0.19 0.05 0.03 0.38 0.00 0.02 0.04 0.08 0.05 0.05 0.07 0.020.02 0.01 SEQID-03733 P20422 — — 0 0.46 0.18 0.06 0.00 0.03 0.08 0.010.01 0.11 0.07 0.03 0.03 0.04 0.09 SEQID-03734 P22613 — — 0 0.39 0.070.01 0.27 0.05 0.04 0.03 0.02 0.00 0.04 0.04 0.00 0.05 0.20 SEQID-03735P22701 — — 0 0.30 0.09 0.04 0.13 0.01 0.05 0.00 0.06 0.18 0.10 0.00 0.020.05 0.10 SEQID-03736 P26351 — — 0 0.49 0.11 0.03 0.00 0.05 0.05 0.000.08 0.19 0.00 0.00 0.02 0.07 0.21 SEQID-03737 P26377 — — 0 0.32 0.060.01 0.22 0.04 0.01 0.05 0.09 0.01 0.02 0.12 0.01 0.02 0.09 SEQID-03738P27013 — — 0 0.37 0.10 0.03 0.14 0.05 0.06 0.03 0.06 0.06 0.02 0.03 0.020.06 0.02 SEQID-03739 P28318 — — 0 0.52 0.22 0.02 0.04 0.04 0.07 0.010.14 0.07 0.02 0.12 0.06 0.10 0.09 SEQID-03740 P28804 — — 0 0.59 0.170.05 0.09 0.05 0.00 0.00 0.02 0.02 0.02 0.00 0.07 0.07 0.23 SEQID-03741P31395 — — 0 0.42 0.14 0.07 0.08 0.05 0.03 0.00 0.05 0.23 0.01 0.03 0.030.09 0.17 SEQID-03742 P32389 — — 1 0.41 0.16 0.03 0.05 0.14 0.08 0.000.04 0.07 0.02 0.05 0.05 0.07 0.08 SEQID-03743 P32450 — — 0 0.38 0.140.01 0.21 0.02 0.04 0.04 0.11 0.01 0.01 0.13 0.06 0.06 0.03 SEQID-03744P37219 — — 0 0.60 0.12 0.08 0.00 0.01 0.04 0.00 0.02 0.17 0.04 0.25 0.030.04 0.18 SEQID-03745 P37220 — — 0 0.56 0.11 0.10 0.04 0.02 0.02 0.000.04 0.14 0.04 0.19 0.03 0.04 0.22 SEQID-03746 P38236 — — 1 0.41 0.150.05 0.04 0.13 0.03 0.00 0.06 0.11 0.01 0.04 0.03 0.09 0.08 SEQID-03747P38243 — — 0 0.45 0.14 0.03 0.07 0.05 0.08 0.00 0.04 0.07 0.01 0.04 0.040.10 0.10 SEQID-03748 P38284 — — 0 0.41 0.13 0.02 0.09 0.06 0.04 0.010.04 0.08 0.03 0.04 0.05 0.06 0.10 SEQID-03749 P39549 — — 1 0.41 0.110.02 0.07 0.06 0.04 0.03 0.04 0.14 0.02 0.03 0.04 0.06 0.04 SEQID-03750P39973 — — 0 0.56 0.16 0.02 0.05 0.05 0.04 0.02 0.01 0.04 0.00 0.06 0.040.09 0.14 SEQID-03751 P41651 — — 0 0.47 0.16 0.06 0.10 0.03 0.07 0.010.00 0.02 0.02 0.02 0.07 0.04 0.20 SEQID-03752 P42755 — — 0 0.31 0.100.04 0.16 0.00 0.03 0.00 0.05 0.22 0.10 0.01 0.02 0.06 0.08 SEQID-03753P46298 — — 1 0.54 0.24 0.04 0.11 0.00 0.04 0.01 0.02 0.05 0.03 0.05 0.090.11 0.15 SEQID-03754 P46517 — — 0 0.32 0.10 0.04 0.15 0.00 0.04 0.000.08 0.17 0.10 0.01 0.01 0.05 0.09 SEQID-03755 P46520 — — 0 0.26 0.090.04 0.15 0.01 0.05 0.00 0.10 0.17 0.11 0.00 0.02 0.04 0.08 SEQID-03756P50415 — — 0 0.32 0.21 0.03 0.19 0.03 0.04 0.02 0.07 0.07 0.02 0.00 0.020.14 0.04 SEQID-03757 P51426 — — 0 0.53 0.10 0.02 0.24 0.05 0.02 0.000.02 0.00 0.01 0.04 0.07 0.03 0.16 SEQID-03758 P52193 — — 1 0.42 0.140.03 0.03 0.04 0.13 0.01 0.04 0.15 0.03 0.02 0.05 0.06 0.11 SEQID-03759P53222 — — 0 0.40 0.14 0.04 0.13 0.09 0.04 0.01 0.03 0.06 0.00 0.02 0.060.05 0.09 SEQID-03760 P53334 — — 1 0.39 0.18 0.10 0.02 0.06 0.06 0.010.05 0.05 0.03 0.01 0.05 0.05 0.06 SEQID-03761 P53869 — — 1 0.48 0.120.01 0.16 0.01 0.05 0.00 0.04 0.05 0.02 0.01 0.02 0.07 0.11 SEQID-03762P60741 — — 0 0.59 0.22 0.04 0.02 0.11 0.04 0.00 0.02 0.08 0.05 0.03 0.070.01 0.26 SEQID-03763 P62144 — — 0 0.44 0.16 0.04 0.04 0.02 0.01 0.120.06 0.05 0.06 0.06 0.08 0.05 0.07 SEQID-03764 P62326 — — 0 0.46 0.090.03 0.00 0.02 0.07 0.00 0.08 0.20 0.01 0.00 0.04 0.04 0.23 SEQID-03765P63212 — — 0 0.45 0.18 0.12 0.06 0.06 0.04 0.03 0.03 0.10 0.00 0.02 0.060.09 0.11 SEQID-03766 P63314 — — 0 0.50 0.11 0.04 0.03 0.02 0.07 0.000.05 0.18 0.01 0.00 0.07 0.05 0.20 SEQID-03767 P67833 — — 0 0.17 0.060.01 0.62 0.00 0.00 0.11 0.02 0.11 0.01 0.02 0.00 0.02 0.00 SEQID-03768P69328 — — 1 0.42 0.17 0.07 0.04 0.04 0.08 0.01 0.03 0.05 0.04 0.01 0.040.07 0.02 SEQID-03769 P79105 — — 0 0.59 0.26 0.02 0.04 0.03 0.10 0.000.06 0.08 0.02 0.06 0.08 0.11 0.12 SEQID-03770 P81451 — — 0 0.56 0.200.06 0.00 0.05 0.06 0.00 0.03 0.07 0.04 0.05 0.06 0.11 0.17 SEQID-03771P83005 — — 0 0.28 0.15 0.05 0.11 0.02 0.10 0.04 0.02 0.11 0.03 0.05 0.020.10 0.00 SEQID-03772 P83489 — — 0 0.28 0.16 0.05 0.08 0.02 0.10 0.040.02 0.12 0.04 0.05 0.02 0.10 0.02 SEQID-03773 P83704 — — 0 0.46 0.210.07 0.02 0.04 0.04 0.01 0.12 0.10 0.01 0.02 0.03 0.14 0.10 SEQID-03774P84088 — — 0 0.38 0.11 0.06 0.08 0.00 0.06 0.01 0.07 0.23 0.04 0.01 0.020.07 0.17 SEQID-03775 P86315 — — 0 0.30 0.14 0.05 0.08 0.02 0.10 0.040.05 0.12 0.04 0.02 0.00 0.10 0.02 SEQID-03776 P94522 — — 1 0.43 0.170.04 0.03 0.08 0.06 0.01 0.03 0.03 0.06 0.01 0.06 0.09 0.07 SEQID-03777Q00747 — — 0 0.46 0.03 0.14 0.07 0.02 0.05 0.00 0.06 0.11 0.06 0.03 0.000.01 0.17 SEQID-03778 Q03323 — — 0 0.39 0.18 0.03 0.03 0.13 0.06 0.010.06 0.12 0.02 0.03 0.05 0.07 0.08 SEQID-03779 Q033K5 — — 0 0.53 0.090.04 0.28 0.02 0.00 0.00 0.02 0.02 0.03 0.05 0.00 0.04 0.19 SEQID-03780Q035G1 — — 0 0.47 0.17 0.07 0.15 0.01 0.05 0.00 0.05 0.03 0.03 0.05 0.030.09 0.16 SEQID-03781 Q035T6 — — 0 0.52 0.15 0.04 0.11 0.04 0.00 0.070.05 0.07 0.02 0.05 0.00 0.06 0.16 SEQID-03782 Q037X5 — — 0 0.46 0.180.04 0.01 0.03 0.10 0.00 0.18 0.06 0.03 0.00 0.06 0.09 0.11 SEQID-03783Q038A1 — — 0 0.55 0.09 0.05 0.18 0.00 0.01 0.00 0.07 0.00 0.02 0.09 0.010.06 0.20 SEQID-03784 Q038J5 — — 0 0.38 0.17 0.06 0.07 0.05 0.07 0.000.05 0.11 0.01 0.03 0.03 0.11 0.06 SEQID-03785 Q038L1 — — 0 0.50 0.130.07 0.09 0.01 0.07 0.01 0.05 0.05 0.03 0.09 0.00 0.08 0.09 SEQID-03786Q039F0 — — 0 0.35 0.11 0.05 0.07 0.06 0.07 0.00 0.04 0.11 0.02 0.04 0.010.08 0.04 SEQID-03787 Q045U8 — — 0 0.46 0.16 0.07 0.04 0.04 0.13 0.000.11 0.04 0.05 0.00 0.05 0.07 0.12 SEQID-03788 Q04664 — — 0 0.58 0.220.05 0.02 0.11 0.04 0.00 0.02 0.08 0.05 0.03 0.07 0.01 0.26 SEQID-03789Q046C1 — — 1 0.57 0.18 0.04 0.09 0.00 0.04 0.00 0.02 0.06 0.04 0.04 0.060.03 0.14 SEQID-03790 Q04C04 — — 0 0.57 0.24 0.07 0.02 0.10 0.03 0.000.00 0.03 0.06 0.02 0.06 0.01 0.22 SEQID-03791 Q04C49 — — 0 0.49 0.110.05 0.05 0.05 0.05 0.01 0.03 0.08 0.04 0.03 0.05 0.02 0.14 SEQID-03792Q06648 — — 1 0.41 0.15 0.03 0.07 0.09 0.05 0.00 0.05 0.06 0.01 0.04 0.040.08 0.09 SEQID-03793 Q08655 — — 0 0.59 0.13 0.08 0.01 0.00 0.04 0.000.01 0.18 0.03 0.19 0.04 0.06 0.20 SEQID-03794 Q08745 — — 1 0.43 0.180.02 0.07 0.04 0.03 0.00 0.09 0.10 0.02 0.03 0.04 0.08 0.09 SEQID-03795Q09MC8 — — 0 0.62 0.15 0.07 0.08 0.06 0.00 0.02 0.00 0.00 0.03 0.00 0.040.10 0.24 SEQID-03796 Q0G9R4 — — 0 0.59 0.16 0.05 0.10 0.06 0.00 0.000.02 0.00 0.04 0.00 0.06 0.07 0.27 SEQID-03797 Q0

J2 — — 0 0.56 0.11 0.09 0.05 0.02 0.02 0.00 0.03 0.03 0.02 0.01 0.030.02 0.34 SEQID-03798 Q

NL7 — — 0 0.46 0.17 0.03 0.05 0.02 0.01 0.13 0.05 0.05 0.07 0.08 0.040.05 0.08 SEQID-03799 Q0MUU2 — — 0 0.37 0.17 0.06 0.07 0.06 0.01 0.010.07 0.12 0.03 0.00 0.07 0.05 0.12 SEQID-03800 Q0VBZ8 — — 1 0.33 0.150.05 0.16 0.02 0.04 0.01 0.05 0.07 0.02 0.02 0.02 0.09 0.04 SEQID-03801Q12034 — — 1 0.38 0.13 0.03 0.05 0.15 0.05 0.00 0.06 0.07 0.02 0.01 0.060.06 0.10 SEQID-03802 Q12087 — — 0 0.49 0.16 0.04 0.15 0.05 0.00 0.000.04 0.04 0.04 0.02 0.00 0.06 0.20 SEQID-03803 Q12515 — — 0 0.42 0.150.04 0.06 0.15 0.07 0.00 0.03 0.06 0.05 0.03 0.07 0.04 0.12 SEQID-03804Q148C4 — — 0 0.36 0.06 0.06 0.07 0.03 0.08 0.00 0.13 0.11 0.05 0.00 0.030.00 0.15 SEQID-03805 Q14FC3 — — 0 0.38 0.20 0.03 0.32 0.03 0.00 0.070.06 0.03 0.03 0.03 0.15 0.05 0.12 SEQID-03806 Q1G9G5 — — 0 0.55 0.230.04 0.01 0.01 0.05 0.00 0.06 0.09 0.05 0.04 0.04 0.03 0.19 SEQID-03807Q1GAQ4 — — 0 0.46 0.17 0.15 0.10 0.05 0.04 0.00 0.06 0.04 0.01 0.02 0.050.08 0.19 SEQID-03808 Q1GBK7 — — 0 0.56 0.24 0.07 0.02 0.10 0.03 0.000.00 0.09 0.06 0.02 0.06 0.01 0.20 SEQID-03809 Q1GBL4 — — 1 0.57 0.170.05 0.09 0.00 0.07 0.00 0.04 0.05 0.03 0.05 0.04 0.04 0.15 SEQID-03810Q1JQB5 — — 1 0.33 0.16 0.06 0.10 0.02 0.06 0.06 0.04 0.09 0.03 0.03 0.030.08 0.05 SEQID-03811 Q29S17 — — 0 0.36 0.20 0.04 0.10 0.03 0.04 0.000.07 0.25 0.01 0.05 0.02 0.15 0.03 SEQID-03812 Q2KU9 — — 0 0.33 0.120.02 0.13 0.02 0.02 0.01 0.04 0.23 0.02 0.02 0.02 0.07 0.08 SEQID-03813Q2KJD8 — — 0 0.36 0.22 0.11 0.19 0.03 0.10 0.01 0.03 0.06 0.06 0.04 0.010.14 0.00 SEQID-03814 Q2L961 — — 0 0.58 0.16 0.06 0.10 0.06 0.00 0.000.02 0.02 0.02 0.00 0.04 0.07 0.23 SEQID-03815 Q2MID0 — — 0 0.55 0.240.01 0.12 0.05 0.02 0.00 0.06 0.07 0.02 0.04 0.07 0.12 0.16 SEQID-03816Q2PMN0 — — 0 0.60 0.12 0.03 0.10 0.05 0.00 0.02 0.02 0.00 0.02 0.00 0.050.05 0.23 SEQID-03817 Q2PMN9 — — 0 0.48 0.22 0.00 0.17 0.03 0.04 0.000.07 0.06 0.02 0.02 0.10 0.09 0.14 SEQID-03818 Q2PMP7 — — 1 0.51 0.250.03 0.08 0.06 0.03 0.02 0.08 0.06 0.04 0.01 0.15 0.05 0.12 SEQID-03819Q2TBJ3 — — 1 0.48 0.20 0.03 0.02 0.06 0.10 0.00 0.00 0.14 0.01 0.02 0.070.08 0.07 SEQID-03820 Q2V2P1 — — 0 0.41 0.13 0.05 0.07 0.08 0.07 0.010.11 0.13 0.00 0.02 0.05 0.06 0.07 SEQID-03821 Q32KM6 — — 1 0.44 0.110.02 0.06 0.05 0.07 0.01 0.06 0.08 0.07 0.02 0.03 0.04 0.12 SEQID-03822Q32KN2 — — 1 0.45 0.17 0.02 0.07 0.04 0.05 0.00 0.04 0.09 0.03 0.04 0.040.10 0.08 SEQID-03823 Q32LI5 — — 1 0.39 0.13 0.03 0.10 0.04 0.06 0.010.07 0.10 0.01 0.01 0.04 0.02 0.14 SEQID-03824 Q32IJ0 — — 0 0.36 0.110.05 0.10 0.01 0.03 0.01 0.16 0.15 0.01 0.00 0.03 0.04 0.15 SEQID-03825Q32PA2 — — 0 0.28 0.12 0.04 0.05 0.01 0.03 0.02 0.09 0.31 0.06 0.03 0.000.08 0.06 SEQID-03826 Q32PA4 — — 1 0.38 0.17 0.06 0.06 0.00 0.10 0.010.05 0.06 0.05 0.04 0.07 0.02 0.09 SEQID-03827 Q32PD7 — — 0 0.42 0.160.08 0.00 0.04 0.20 0.00 0.02 0.10 0.05 0.02 0.02 0.09 0.04 SEQID-03828Q332T8 — — 1 0.49 0.24 0.03 0.10 0.05 0.03 0.01 0.08 0.08 0.04 0.02 0.150.06 0.10 SEQID-03829 Q3E742 — — 0 0.54 0.12 0.04 0.06 0.07 0.00 0.030.05 0.08 0.03 0.05 0.01 0.06 0.30 SEQID-03830 Q3E764 — — 0 0.52 0.110.07 0.02 0.02 0.07 0.00 0.11 0.04 0.06 0.00 0.03 0.07 0.31 SEQID-03831Q3E807 — — 1 0.56 0.17 0.01 0.05 0.04 0.03 0.02 0.03 0.04 0.01 0.05 0.050.08 0.12 SEQID-03832 Q3I5G7 — — 0 0.44 0.17 0.09 0.00 0.02 0.05 0.000.05 0.17 0.07 0.01 0.02 0.03 0.13 SEQID-03833 Q3MIC0 — — 1 0.56 0.160.06 0.11 0.01 0.01 0.04 0.02 0.09 0.05 0.03 0.06 0.03 0.19 SEQID-03834Q35WY1 — — 1 0.39 0.16 0.06 0.09 0.01 0.03 0.02 0.04 0.09 0.05 0.04 0.010.11 0.09 SEQID-03835 Q3T051 — — 0 0.54 0.12 0.01 0.22 0.05 0.00 0.000.06 0.00 0.02 0.04 0.07 0.05 0.18 SEQID-03836 Q3T0F2 — — 1 0.55 0.180.04 0.05 0.06 0.08 0.00 0.02 0.06 0.02 0.07 0.04 0.08 0.07 SEQID-03837Q3V4Y6 — — 0 0.57 0.13 0.05 0.10 0.04 0.00 0.00 0.04 0.02 0.02 0.00 0.030.03 0.24 SEQID-03838 Q3V500 — — 0 0.42 0.22 0.02 0.28 0.03 0.00 0.070.06 0.03 0.03 0.03 0.15 0.03 0.14 SEQID-03839 Q3ZBD4 — — 0 0.35 0.160.06 0.07 0.06 0.01 0.01 0.07 0.12 0.04 0.00 0.09 0.04 0.12 SEQID-03840Q41784 — — 1 0.43 0.17 0.04 0.07 0.05 0.06 0.02 0.05 0.10 0.04 0.03 0.040.08 0.04 SEQID-03841 Q4VZK0 — — 1 0.49 0.26 0.02 0.17 0.07 0.03 0.010.02 0.05 0.04 0.02 0.15 0.08 0.07 SEQID-03842 Q4VZL1 — — 0 0.49 0.220.00 0.12 0.05 0.02 0.00 0.07 0.08 0.02 0.03 0.02 0.12 0.16 SEQID-03843Q4VZN0 — — 1 0.48 0.25 0.03 0.10 0.05 0.01 0.04 0.08 0.07 0.05 0.02 0.140.06 0.09 SEQID-03844 Q5E9A0 — — 1 0.37 0.15 0.05 0.09 0.02 0.06 0.030.05 0.08 0.03 0.03 0.02 0.07 0.08 SEQID-03845 Q5EAE6 — — 1 0.41 0.100.06 0.08 0.00 0.07 0.00 0.08 0.07 0.04 0.09 0.05 0.01 0.11 SEQID-03846Q5F3Z5 — — 1 0.40 0.10 0.04 0.10 0.04 0.05 0.00 0.04 0.11 0.06 0.03 0.020.05 0.09 SEQID-03847 Q5

W8 — — 0 0.58 0.07 0.05 0.20 0.01 0.01 0.00 0.05 0.00 0.03 0.12 0.010.03 0.18 SEQID-03848 Q5FKE7 — — 0 0.32 0.10 0.05 0.07 0.04 0.09 0.000.07 0.11 0.00 0.01 0.00 0.07 0.04 SEQID-03849 Q5FM68 — — 0 0.52 0.160.02 0.14 0.03 0.00 0.07 0.06 0.03 0.03 0.09 0.05 0.00 0.17 SEQID-03850Q5FM86 — — 1 0.55 0.17 0.05 0.07 0.00 0.09 0.00 0.04 0.02 0.03 0.05 0.050.04 0.13 SEQID-03851 Q5SMI4 — — 0 0.53 0.10 0.02 0.22 0.05 0.02 0.000.04 0.00 0.01 0.04 0.07 0.03 0.16 SEQID-03852 Q5ZMM5 — — 0 0.46 0.090.08 0.04 0.01 0.04 0.02 0.18 0.05 0.01 0.05 0.03 0.04 0.19 SEQID-03853Q5ZMN0 — — 0 0.34 0.20 0.01 0.05 0.06 0.17 0.01 0.01 0.23 0.03 0.01 0.030.14 0.06 SEQID-03854 Q6SMX0 — — 1 0.46 0.16 0.05 0.06 0.05 0.08 0.000.05 0.06 0.05 0.06 0.04 0.06 0.07 SEQID-03855 Q66QC7 — — 0 0.09 0.060.01 0.65 0.00 0.00 0.12 0.04 0.00 0.00 0.00 0.00 0.02 0.00 SEQID-03856Q6RFL5 — — 1 0.44 0.18 0.05 0.09 0.02 0.04 0.00 0.04 0.10 0.02 0.09 0.030.12 0.06 SEQID-03857 Q74IL4 — — 0 0.59 0.21 0.03 0.01 0.01 0.04 0.000.03 0.10 0.04 0.04 0.05 0.02 0.22 SEQID-03858 Q74L00 — — 0 0.49 0.160.07 0.03 0.05 0.12 0.00 0.10 0.04 0.05 0.00 0.05 0.07 0.14 SEQID-03859Q74LZ9 — — 0 0.53 0.16 0.06 0.03 0.00 0.08 0.00 0.04 0.18 0.06 0.02 0.040.04 0.29 SEQID-03860 Q7DMN9 — — 0 0.45 0.17 0.03 0.05 0.03 0.01 0.130.05 0.05 0.07 0.08 0.07 0.04 0.08 SEQID-03861 Q7M2P1 — — 0 0.49 0.100.02 0.21 0.01 0.00 0.01 0.06 0.03 0.01 0.02 0.04 0.01 0.22 SEQID-03862Q7XC27 — — 1 0.50 0.21 0.03 0.08 0.05 0.09 0.00 0.02 0.10 0.02 0.01 0.070.09 0.07 SEQID-03863 Q7YQJ3 — — 0 0.27 0.13 0.06 0.08 0.01 0.10 0.010.05 0.15 0.06 0.00 0.03 0.04 0.03 SEQID-03864 Q88VD4 — — 0 0.44 0.140.15 0.12 0.08 0.06 0.00 0.01 0.03 0.01 0.00 0.05 0.04 0.17 SEQID-03865Q88WD3 — — 0 0.50 0.12 0.06 0.04 0.01 0.14 0.00 0.05 0.10 0.04 0.00 0.000.04 0.27 SEQID-03866 Q88WM6 — — 0 0.40 0.18 0.06 0.00 0.07 0.05 0.000.17 0.17 0.03 0.00 0.01 0.12 0.06 SEQID-03867 Q88WN5 — — 0 0.55 0.190.06 0.04 0.01 0.07 0.00 0.07 0.05 0.06 0.02 0.05 0.01 0.16 SEQID-03868Q88WU7 — — 0 0.59 0.12 0.07 0.13 0.03 0.00 0.00 0.07 0.02 0.02 0.06 0.050.05 0.24 SEQID-03869 Q88XY2 — — 1 0.57 0.17 0.09 0.08 0.00 0.10 0.000.02 0.01 0.04 0.07 0.07 0.04 0.15 SEQID-03870 Q88YP9 — — 0 0.52 0.140.06 0.01 0.04 0.12 0.00 0.11 0.03 0.03 0.00 0.02 0.05 0.11 SEQID-03871Q8G435 — — 0 0.44 0.12 0.03 0.19 0.05 0.03 0.06 0.02 0.08 0.02 0.02 0.050.05 0.12 SEQID-03872 Q8GC82 — — 1 0.47 0.20 0.03 0.05 0.12 0.06 0.000.01 0.04 0.05 0.03 0.09 0.05 0.08 SEQID-03873 Q8HYY9 — — 0 0.26 0.160.06 0.11 0.02 0.10 0.04 0.02 0.12 0.04 0.05 0.04 0.10 0.00 SEQID-03874Q8TGT3 — — 0 0.62 0.22 0.00 0.12 0.00 0.03 0.03 0.03 0.06 0.00 0.00 0.060.11 0.16 SEQID-03875 Q8TGU1 — — 0 0.48 0.17 0.00 0.06 0.09 0.04 0.040.02 0.15 0.03 0.05 0.04 0.11 0.14 SEQID-03876 Q8TGV0 — — 0 0.26 0.140.00 0.28 0.03 0.00 0.03 0.08 0.00 0.00 0.00 0.03 0.10 0.04 SEQID-03877Q90953 — — 1 0.45 0.18 0.04 0.04 0.03 0.06 0.01 0.04 0.12 0.03 0.03 0.050.06 0.06 SEQID-03878 Q96386 — — 0 0.39 0.09 0.05 0.00 0.05 0.10 0.150.02 0.06 0.04 0.02 0.05 0.00 0.11 SEQID-03879 Q98TFS — — 0 0.56 0.120.01 0.20 0.05 0.00 0.00 0.06 0.00 0.02 0.04 0.07 0.05 0.20 SEQID-03880Q9DET5 — — 0 0.52 0.12 0.00 0.00 0.04 0.07 0.04 0.02 0.20 0.00 0.00 0.020.06 0.27 SEQID-03881 Q9N250 — — 0 0.49 0.20 0.09 0.00 0.03 0.03 0.000.06 0.19 0.04 0.01 0.02 0.01 0.15 SEQID-03882 Q9P305 — — 0 0.39 0.180.04 0.10 0.06 0.08 0.00 0.04 0.04 0.04 0.02 0.05 0.09 0.11 SEQID-03883Q9SP22 — — 1 0.44 0.14 0.05 0.02 0.03 0.14 0.00 0.03 0.12 0.03 0.03 0.060.05 0.14 SEQID-03884 Q9URQ5 — — 0 0.42 0.19 0.02 0.10 0.14 0.01 0.010.06 0.13 0.00 0.01 0.05 0.12 0.08 SEQID-03885 Q9XSK7 — — 1 0.34 0.090.05 0.06 0.03 0.05 0.01 0.02 0.23 0.05 0.02 0.01 0.06 0.13 SEQID-03886Q92T46 — — 0 0.50 0.20 0.03 0.04 0.04 0.08 0.00 0.05 0.07 0.06 0.04 0.070.07 0.10 SEQID-03887 Q9ZT47 — — 0 0.51 0.18 0.03 0.03 0.04 0.08 0.010.02 0.08 0.07 0.06 0.06 0.07 0.12 SEQID-03888 Q9ZZV8 — — 0 0.39 0.070.02 0.16 0.08 0.04 0.00 0.00 0.02 0.04 0.00 0.02 0.02 0.13 SEQID-03889W5PEW5 — — 1 0.42 0.20 0.03 0.06 0.04 0.04 0.01 0.10 0.18 0.01 0.02 0.030.13 0.11 SEQID-03890 Q2YDE5 —  6:66 0 0.45 0.23 0.00 0.09 0.08 0.000.06 0.04 0.02 0.22 0.16 0.02 0.00 0.02 SEQID-03891 Q06698 — 151:201 00.57 0.16 0.00 0.07 0.00 0.04 0.13 0.10 0.02 0.13 0.14 0.06 0.01 0.07SEQID-03892 P53061 — 251:301 0 0.57 0.14 0.00 0.07 0.00 0.02 0.05 0.050.05 0.07 0.24 0.02 0.01 0.11 SEQID-03893 P53061 — 251:306 0 0.56 0.140.00 0.06 0.00 0.02 0.05 0.04 0.05 0.08 0.24 0.02 0.01 0.10 SEQID-03894P53061 — 251:311 0 0.56 0.16 0.00 0.06 0.00 0.02 0.08 0.04 0.04 0.100.23 0.02 0.01 0.10 SEQID-03895 P53061 — 251:316 0 0.57 0.17 0.00 0.060.00 0.02 0.08 0.04 0.04 0.11 0.22 0.02 0.01 0.09 SEQID-03896 Q90980 —381:431 0 0.58 0.26 0.00 0.04 0.00 0.02 0.07 0.10 0.07 0.11 0.16 0.020.03 0.02 SEQID-03897 Q00194 — 426:476 0 0.60 0.24 0.00 0.04 0.00 0.020.09 0.10 0.05 0.11 0.18 0.02 0.02 0.02 SEQID-03898 Q00194 — 426:481 00.59 0.24 0.00 0.03 0.00 0.02 0.10 0.09 0.07 0.10 0.17 0.02 0.03 0.04SEQID-03899 Q90805 — 466:521 0 0.67 0.24 0.00 0.05 0.00 0.04 0.09 0.050.05 0.12 0.21 0.02 0.03 0.04 SEQID-03900 Q35Z12 —  86:136 0 0.57 0.210.00 0.07 0.00 0.02 0.04 0.10 0.09 0.05 0.23 0.04 0.03 0.02 SEQID-03901P04467 — 121:171 0 0.56 0.25 0.01 0.08 0.01 0.00 0.12 0.03 0.00 0.230.15 0.04 0.04 0.05 SEQID-03902 Q0P584 — 166:216 0 0.51 0.23 0.00 0.020.03 0.02 0.06 0.20 0.00 0.22 0.14 0.04 0.02 0.02 SEQID-03903 Q2NL14 —211:261 0 0.52 0.24 0.03 0.04 0.03 0.07 0.00 0.15 0.00 0.22 0.17 0.000.02 0.02 SEQID-03904 Q10MN8 — 211:276 0 0.32 0.25 0.01 0.01 0.05 0.040.06 0.20 0.01 0.22 0.00 0.02 0.09 0.02 SEQID-03905 P58797 — 266:316 00.47 0.31 0.02 0.06 0.08 0.00 0.08 0.08 0.02 0.26 0.16 0.00 0.05 0.00SEQID-03906 A7A1V1 — 41:91 0 0.49 0.33 0.02 0.06 0.03 0.02 0.09 0.130.07 0.24 0.08 0.00 0.00 0.00 SEQID-03907 P50275 — 491:546 0 0.47 0.270.00 0.03 0.04 0.00 0.05 0.05 0.03 0.22 0.08 0.00 0.01 0.07 SEQID-03908Q60CZ8 — 591:646 0 0.42 0.29 0.01 0.03 0.04 0.00 0.16 0.14 0.03 0.220.04 0.02 0.03 0.00 SEQID-03909 Q9AWA5 — 821:876 0 0.45 0.30 0.01 0.050.01 0.02 0.09 0.14 0.02 0.22 0.06 0.00 0.03 0.02 Aller- SolveScoreNetChg genHo- Aller- Tox- Anti- SEQID M F P S T W Y V (pH 7) AggScore(pH 7) pI mology genicity icity nutricity SEQID-00001 0.05 0.07 0.030.03 0.04 0.01 0.04 0.07 −18.29 0.50 −0.03 4.96 1.00 1.00 0.20 0.42SEQID-00002 0.02 0.06 0.05 0.05 0.03 0.01 0.03 0.05 −18.75 0.40 −0.015.25 1.00 1.00 0.19 0.21 SEQID-00003 0.03 0.03 0.04 0.03 0.05 0.02 0.030.04 −20.98 0.56 −0.04 4.66 1.00 1.00 0.00 0.24 SEQID-00004 0.03 0.050.07 0.06 0.02 0.02 0.07 0.05 −21.19 0.32 −0.05 4.70 1.00 1.00 0.23 0.23SEQID-00005 0.04 0.05 0.14 0.06 0.04 0.01 0.03 0.08 −15.50 0.50 −0.035.06 1.00 1.00 0.24 0.12 SEQID-00006 0.02 0.05 0.01 0.05 0.05 0.05 0.040.05 −20.52 0.44 −0.04 4.73 1.00 1.00 0.26 0.25 SEQID-00007 0.00 0.020.01 0.03 0.00 0.00 0.15 0.03 −28.17 0.11 0.00 6.98 0.29 0.19 0.37 0.33SEQID-00008 0.05 0.08 0.01 0.04 0.05 0.00 0.02 0.05 −30.62 0.31 −0.213.67 0.95 0.98 0.23 0.00 SEQID-00009 0.02 0.02 0.03 0.03 0.02 0.00 0.020.03 −38.14 0.22 −0.28 3.59 0.23 0.41 0.23 0.25 SEQID-00010 0.03 0.050.07 0.06 0.03 0.00 0.04 0.06 −5.26 0.69 0.01 9.42 0.28 0.39 0.25 0.00SEQID-00011 0.03 0.07 0.04 0.03 0.05 0.01 0.07 0.06 −21.57 0.36 −0.025.81 0.25 0.32 0.24 0.00 SEQID-00012 0.00 0.02 0.01 0.03 0.00 0.00 0.150.03 −28.17 0.11 0.00 6.98 0.29 0.19 0.37 0.33 SEQID-00013 0.00 0.020.02 0.03 0.00 0.00 0.16 0.03 −27.17 0.12 0.00 7.00 0.30 0.19 0.38 0.34SEQID-00014 0.00 0.02 0.02 0.03 0.00 0.00 0.13 0.03 −28.08 0.11 0.027.69 0.31 0.20 0.38 0.31 SEQID-00015 0.00 0.03 0.02 0.03 0.00 0.00 0.140.04 −27.01 0.12 0.02 7.75 0.31 0.13 0.38 0.28 SEQID-00016 0.05 0.030.04 0.04 0.04 0.02 0.03 0.02 −20.72 0.65 −0.13 3.73 0.40 0.44 0.26 0.25SEQID-00017 0.05 0.10 0.04 0.05 0.02 0.02 0.06 0.04 −19.76 0.63 −0.123.86 0.48 0.51 0.00 0.30 SEQID-00018 0.04 0.06 0.00 0.05 0.02 0.05 0.080.02 −20.08 0.50 0.25 12.35 0.22 0.24 0.00 0.24 SEQID-00019 0.00 0.100.00 0.00 0.00 0.00 0.00 0.06 −27.12 0.34 0.37 13.87 0.26 0.28 0.00 0.25SEQID-00020 0.03 0.10 0.03 0.05 0.03 0.00 0.04 0.05 −19.74 0.39 0.1310.85 0.42 0.47 0.25 0.26 SEQID-00021 0.02 0.00 0.05 0.06 0.03 0.00 0.120.07 −17.96 0.43 0.12 10.56 0.26 0.30 0.25 0.00 SEQID-00022 0.03 0.050.08 0.05 0.04 0.00 0.05 0.06 −4.43 0.72 0.01 8.97 0.29 0.39 0.25 0.00SEQID-00023 0.01 0.01 0.06 0.06 0.00 0.00 0.03 0.05 −6.27 0.79 0.02 9.330.36 0.39 0.00 0.00 SEQID-00024 0.00 0.07 0.04 0.02 0.06 0.00 0.00 0.10−15.79 0.80 −0.03 4.45 0.28 0.31 0.00 1.00 SEQID-00025 0.00 0.05 0.030.06 0.04 0.00 0.00 0.03 −16.50 0.84 0.08 3.94 0.25 0.29 0.00 1.00SEQID-00026 0.00 0.05 0.00 0.00 0.03 0.07 0.00 0.03 −9.16 2.04 −0.044.15 0.28 0.32 0.24 0.26 SEQID-00027 0.02 0.02 0.03 0.04 0.03 0.00 0.120.09 −16.31 0.80 −0.05 4.39 0.23 0.32 0.00 0.00 SEQID-00028 0.00 0.030.01 0.03 0.05 0.00 0.03 0.15 −21.97 1.00 −0.25 3.10 0.28 0.30 0.00 0.25SEQID-00029 0.03 0.01 0.02 0.04 0.02 0.00 0.13 0.06 −24.09 0.41 −0.123.93 0.00 0.31 0.00 0.00 SEQID-00030 0.00 0.00 0.00 0.05 0.08 0.00 0.000.05 −28.44 0.16 −0.04 4.97 0.33 0.36 0.00 0.00 SEQID-00031 0.00 0.000.00 0.02 0.04 0.00 0.01 0.04 −36.33 0.16 −0.04 4.90 0.32 0.33 0.00 0.00SEQID-00032 0.02 0.00 0.00 0.03 0.06 0.00 0.00 0.03 −36.17 0.22 −0.124.27 0.32 0.35 0.25 0.27 SEQID-00033 0.02 0.00 0.01 0.04 0.06 0.02 0.010.07 −27.36 0.49 0.01 8.97 0.30 0.34 0.00 0.30 SEQID-00034 0.04 0.000.03 0.03 0.05 0.03 0.03 0.04 −20.74 0.58 0.00 6.54 0.84 0.34 0.29 0.28SEQID-00035 0.02 0.01 0.04 0.05 0.06 0.00 0.00 0.09 −18.18 0.64 0.0510.26 0.26 0.30 0.00 0.00 SEQID-00036 0.02 0.08 0.01 0.03 0.04 0.06 0.060.06 −17.32 0.73 0.03 8.48 0.51 0.60 0.26 0.24 SEQID-00037 0.06 0.070.00 0.00 0.10 0.05 0.00 0.09 −14.15 1.56 0.19 11.98 0.14 0.26 0.23 0.24SEQID-00038 0.01 0.06 0.03 0.06 0.02 0.08 0.01 0.07 −19.01 0.72 0.007.29 0.26 0.33 0.25 0.27 SEQID-00039 0.02 0.06 0.02 0.03 0.03 0.02 0.050.06 −24.37 0.51 0.05 9.49 0.27 0.30 0.24 0.26 SEQID-00040 0.00 0.080.04 0.02 0.05 0.00 0.03 0.11 −17.17 0.77 −0.03 4.50 0.27 0.31 0.00 1.00SEQID-00041 0.03 0.06 0.01 0.05 0.03 0.05 0.08 0.02 −21.00 0.47 0.2212.17 0.19 0.25 0.00 0.00 SEQID-00042 0.01 0.04 0.12 0.11 0.06 0.00 0.060.04 −24.24 0.16 −0.21 3.55 0.29 0.32 0.26 0.30 SEQID-00043 0.00 0.050.04 0.00 0.05 0.00 0.00 0.11 −17.59 0.99 −0.02 4.77 0.32 0.20 0.00 1.00SEQID-00044 0.00 0.05 0.03 0.00 0.05 0.00 0.00 0.11 −17.59 1.04 −0.024.77 0.32 0.20 0.00 1.00 SEQID-00045 0.00 0.03 0.03 0.02 0.05 0.00 0.000.10 −18.20 0.93 −0.04 4.46 0.32 0.21 0.00 1.00 SEQID-00046 0.00 0.030.03 0.02 0.05 0.00 0.00 0.10 −18.55 0.92 −0.04 4.46 0.33 0.21 0.33 1.00SEQID-00047 0.00 0.03 0.04 0.02 0.06 0.00 0.00 0.11 −16.30 1.04 −0.044.39 0.35 0.22 0.00 1.00 SEQID-00048 0.00 0.00 0.05 0.06 0.05 0.00 0.000.00 −4.65 0.00 0.64 13.78 0.38 0.15 0.44 0.39 SEQID-00049 0.02 0.060.03 0.03 0.07 0.01 0.05 0.06 −21.74 0.30 −0.01 6.61 0.23 0.31 0.23 0.00SEQID-00050 0.02 0.10 0.09 0.00 0.02 0.00 0.00 0.09 −16.62 0.92 0.059.51 1.00 0.63 0.00 0.34 SEQID-00051 0.00 0.10 0.09 0.00 0.02 0.00 0.000.09 −17.98 0.90 0.07 10.22 1.00 0.63 0.00 0.00 SEQID-00052 0.00 0.100.09 0.00 0.02 0.00 0.00 0.11 −16.59 0.95 0.05 9.51 1.00 0.63 0.00 0.32SEQID-00053 0.00 0.10 0.09 0.00 0.02 0.00 0.00 0.11 −16.79 0.87 0.059.51 1.00 0.63 0.00 0.33 SEQID-00054 0.00 0.10 0.09 0.00 0.02 0.00 0.000.11 −18.37 0.77 0.03 8.55 1.00 0.63 0.00 0.30 SEQID-00055 0.00 0.100.09 0.00 0.02 0.00 0.00 0.11 −18.37 0.71 0.03 8.55 1.00 0.63 0.00 0.32SEQID-00056 0.00 0.00 0.05 0.09 0.00 0.00 0.08 0.08 −26.42 0.21 −0.044.99 1.00 0.63 0.26 0.00 SEQID-00057 0.00 0.00 0.07 0.09 0.00 0.00 0.080.08 −24.84 0.25 −0.03 5.78 1.00 0.63 0.26 0.00 SEQID-00058 0.00 0.000.07 0.07 0.00 0.00 0.08 0.08 −24.93 0.20 −0.02 5.78 1.00 0.63 0.26 0.00SEQID-00059 0.00 0.00 0.07 0.04 0.00 0.00 0.08 0.08 −26.10 0.22 0.007.53 1.00 0.63 0.26 0.00 SEQID-00060 0.02 0.06 0.03 0.03 0.06 0.01 0.050.06 −24.08 0.29 −0.11 4.40 0.22 0.31 0.23 0.30 SEQID-00061 0.02 0.060.03 0.03 0.05 0.01 0.05 0.06 −25.02 0.25 0.16 11.10 0.22 0.30 0.23 0.00SEQID-00062 0.01 0.07 0.02 0.04 0.04 0.00 0.01 0.11 −10.77 1.44 0.038.52 0.25 0.29 0.27 0.28 SEQID-00063 0.04 0.05 0.04 0.07 0.05 0.00 0.080.09 −5.74 1.81 −0.03 4.13 0.37 0.30 0.24 0.23 SEQID-00064 0.02 0.060.03 0.07 0.04 0.01 0.10 0.06 −6.82 1.66 −0.04 3.88 0.23 0.28 0.22 0.25SEQID-00065 0.03 0.03 0.04 0.06 0.05 0.02 0.01 0.08 −5.87 1.50 0.0210.29 0.22 0.31 0.24 0.24 SEQID-00066 0.01 0.16 0.03 0.03 0.02 0.00 0.070.10 −10.37 1.56 0.03 9.86 0.25 0.31 0.22 0.22 SEQID-00067 0.02 0.050.03 0.05 0.05 0.01 0.07 0.09 −7.86 1.69 0.03 9.42 0.23 0.29 0.22 0.24SEQID-00068 0.01 0.00 0.00 0.06 0.02 0.01 0.06 0.10 −21.10 0.87 −0.054.70 0.76 0.88 0.00 0.20 SEQID-00069 0.01 0.01 0.03 0.06 0.04 0.00 0.000.12 −14.66 1.17 −0.08 3.87 0.26 0.29 0.00 0.88 SEQID-00070 0.01 0.030.03 0.06 0.04 0.00 0.00 0.09 −16.34 0.91 −0.08 3.94 0.23 0.28 0.00 0.95SEQID-00071 0.00 0.05 0.02 0.00 0.05 0.00 0.00 0.14 −17.59 1.19 −0.024.77 0.32 0.20 0.00 0.94 SEQID-00072 0.08 0.07 0.01 0.02 0.04 0.00 0.030.04 −31.39 0.32 −0.18 3.79 0.37 0.43 0.21 0.22 SEQID-00073 0.03 0.050.00 0.02 0.04 0.03 0.01 0.05 −32.67 0.32 −0.10 4.22 0.39 0.54 0.26 0.25SEQID-00074 0.08 0.08 0.01 0.03 0.03 0.00 0.02 0.04 −30.64 0.26 −0.183.81 0.38 0.45 0.25 0.22 SEQID-00075 0.08 0.07 0.01 0.02 0.04 0.00 0.030.04 −31.40 0.32 −0.18 3.79 0.37 0.43 0.21 0.22 SEQID-00076 0.08 0.070.01 0.02 0.04 0.00 0.03 0.04 −31.40 0.32 −0.18 3.79 0.37 0.43 0.21 0.22SEQID-00077 0.05 0.09 0.01 0.04 0.06 0.00 0.01 0.04 −29.63 0.32 −0.213.61 1.00 1.00 0.25 0.00 SEQID-00078 0.03 0.07 0.01 0.01 0.04 0.00 0.030.04 −31.05 0.32 −0.19 3.74 0.37 0.41 0.21 0.20 SEQID-00079 0.04 0.070.08 0.03 0.02 0.03 0.03 0.06 −13.19 1.21 0.09 10.26 0.32 0.21 0.27 0.28SEQID-00080 0.02 0.14 0.04 0.07 0.05 0.03 0.06 0.04 −9.71 1.15 −0.025.52 0.21 0.31 0.23 0.24 SEQID-00081 0.05 0.09 0.01 0.09 0.01 0.05 0.060.04 −12.67 1.02 0.04 8.87 0.26 0.27 0.29 0.00 SEQID-00082 0.02 0.030.04 0.05 0.04 0.03 0.02 0.08 −14.94 0.85 0.03 8.78 0.00 0.33 0.23 0.23SEQID-00083 0.05 0.04 0.09 0.06 0.05 0.02 0.02 0.04 −15.80 0.76 0.0810.61 0.28 0.24 0.30 0.30 SEQID-00084 0.04 0.02 0.01 0.01 0.02 0.03 0.050.02 −24.13 0.24 −0.21 3.63 0.68 0.52 0.32 0.31 SEQID-00085 0.05 0.070.02 0.02 0.05 0.00 0.04 0.08 −23.50 0.38 −0.09 4.29 0.37 0.46 0.00 0.18SEQID-00086 0.07 0.07 0.02 0.03 0.05 0.00 0.03 0.07 −23.76 0.32 −0.084.24 0.36 0.45 0.22 0.23 SEQID-00087 0.05 0.09 0.02 0.03 0.05 0.00 0.010.05 −23.80 0.35 −0.08 4.24 0.37 0.49 0.23 0.27 SEQID-00088 0.05 0.060.07 0.08 0.02 0.02 0.08 0.02 −15.45 0.39 −0.08 3.93 0.29 0.32 1.00 0.34SEQID-00089 0.03 0.05 0.02 0.05 0.05 0.02 0.04 0.06 −28.87 0.28 −0.074.48 0.43 0.63 0.00 0.21 SEQID-00090 0.05 0.07 0.03 0.05 0.05 0.02 0.050.06 −19.97 0.34 −0.06 4.45 0.40 0.54 0.00 0.21 SEQID-00091 0.03 0.060.04 0.05 0.06 0.02 0.06 0.07 −19.21 0.44 −0.05 4.51 0.92 0.99 0.00 0.00SEQID-00092 0.08 0.08 0.01 0.03 0.03 0.00 0.02 0.04 −30.84 0.27 −0.183.81 0.37 0.45 0.25 0.23 SEQID-00093 0.08 0.09 0.01 0.03 0.04 0.00 0.000.03 −30.31 0.28 −0.18 3.81 0.38 0.47 0.25 0.24 SEQID-00094 0.09 0.090.01 0.03 0.04 0.00 0.00 0.03 −30.14 0.30 −0.18 3.81 0.37 0.47 0.25 0.23SEQID-00095 0.03 0.02 0.04 0.04 0.06 0.01 0.02 0.07 −21.15 0.62 −0.064.42 0.65 0.74 0.00 0.23 SEQID-00096 0.02 0.05 0.01 0.05 0.05 0.05 0.040.05 −21.02 0.44 −0.05 4.61 0.99 1.00 0.26 0.26 SEQID-00097 0.03 0.000.00 0.03 0.02 0.00 0.03 0.02 −36.52 0.12 −0.10 4.38 0.58 0.70 0.25 0.21SEQID-00098 0.03 0.07 0.00 0.02 0.05 0.00 0.02 0.11 −33.16 0.40 −0.253.57 0.27 0.24 0.34 0.00 SEQID-00099 0.03 0.05 0.03 0.05 0.01 0.00 0.000.11 −27.07 0.41 −0.19 3.67 0.31 0.30 0.41 0.24 SEQID-00100 0.03 0.080.01 0.05 0.03 0.00 0.02 0.04 −29.97 0.29 −0.21 3.67 0.35 0.35 0.42 0.30SEQID-00101 0.03 0.05 0.00 0.09 0.02 0.00 0.02 0.10 −29.38 0.37 −0.153.90 0.23 0.29 0.38 0.23 SEQID-00102 0.04 0.08 0.01 0.04 0.04 0.00 0.020.04 −30.86 0.24 −0.20 3.75 0.30 0.30 0.38 0.00 SEQID-00103 0.08 0.070.01 0.03 0.06 0.00 0.01 0.05 −27.55 0.34 −0.16 3.79 0.39 0.46 0.22 0.24SEQID-00104 0.07 0.07 0.01 0.02 0.05 0.00 0.01 0.05 −28.96 0.24 −0.153.88 0.43 0.49 0.22 0.21 SEQID-00105 0.04 0.07 0.01 0.10 0.03 0.00 0.000.04 −23.64 0.35 −0.13 3.92 0.39 0.46 0.25 0.26 SEQID-00106 0.07 0.080.01 0.03 0.05 0.00 0.01 0.05 −29.02 0.23 −0.15 3.87 0.44 0.51 0.23 0.21SEQID-00107 0.01 0.06 0.05 0.03 0.03 0.04 0.05 0.04 −30.63 0.26 −0.134.06 0.32 0.49 0.00 0.22 SEQID-00108 0.01 0.04 0.05 0.04 0.04 0.05 0.060.03 −31.29 0.25 −0.10 4.28 0.34 0.55 0.00 0.22 SEQID-00109 0.00 0.030.03 0.03 0.03 0.03 0.06 0.14 −21.85 0.87 −0.26 2.83 0.31 0.21 0.27 0.35SEQID-00110 0.00 0.03 0.02 0.05 0.04 0.06 0.03 0.02 −25.30 0.46 −0.183.78 0.36 0.22 0.33 0.34 SEQID-00111 0.02 0.00 0.05 0.01 0.02 0.03 0.050.03 −27.81 0.25 −0.10 4.35 0.33 0.21 0.34 0.29 SEQID-00112 0.06 0.070.03 0.00 0.02 0.03 0.05 0.03 −22.49 0.43 −0.13 3.90 0.33 0.21 0.31 0.35SEQID-00113 0.04 0.11 0.01 0.02 0.01 0.03 0.02 0.03 −22.06 0.51 −0.134.12 0.29 0.21 0.28 0.27 SEQID-00114 0.05 0.05 0.05 0.02 0.05 0.03 0.000.12 −28.91 0.42 −0.16 4.04 0.37 0.20 0.28 0.37 SEQID-00115 0.02 0.010.03 0.04 0.11 0.00 0.03 0.03 −38.34 0.23 −0.32 3.45 0.31 0.35 0.26 0.33SEQID-00116 0.02 0.01 0.03 0.04 0.11 0.00 0.03 0.04 −37.93 0.23 −0.313.46 0.31 0.35 0.26 0.33 SEQID-00117 0.03 0.10 0.02 0.02 0.03 0.03 0.050.05 −21.01 0.41 −0.10 4.21 0.24 0.31 0.00 0.28 SEQID-00118 0.03 0.120.02 0.04 0.03 0.02 0.01 0.03 −23.16 0.43 −0.10 4.17 0.23 0.28 0.00 0.00SEQID-00119 0.04 0.05 0.03 0.04 0.03 0.02 0.03 0.10 −23.37 0.44 −0.124.07 0.28 0.29 0.25 0.24 SEQID-00120 0.02 0.06 0.03 0.04 0.05 0.02 0.030.09 −25.42 0.36 −0.12 4.08 0.28 0.30 0.00 0.26 SEQID-00121 0.02 0.030.08 0.04 0.07 0.00 0.12 0.05 −25.73 0.12 −0.21 3.49 0.25 0.39 0.00 0.27SEQID-00122 0.01 0.03 0.06 0.05 0.07 0.00 0.13 0.05 −27.56 0.08 −0.223.50 0.00 0.31 0.24 0.24 SEQID-00123 0.01 0.05 0.01 0.06 0.08 0.02 0.030.06 −26.58 0.34 −0.13 4.03 0.48 0.59 0.00 0.22 SEQID-00124 0.02 0.050.02 0.05 0.08 0.02 0.03 0.06 −27.93 0.29 −0.12 4.12 0.50 0.61 0.00 0.25SEQID-00125 0.02 0.03 0.02 0.10 0.04 0.01 0.06 0.09 −17.21 0.63 −0.103.73 0.24 0.32 0.00 0.22 SEQID-00126 0.01 0.05 0.07 0.11 0.05 0.01 0.050.03 −25.09 0.15 −0.18 3.64 0.23 0.33 0.00 0.26 SEQID-00127 0.03 0.020.04 0.04 0.06 0.01 0.02 0.07 −21.15 0.62 −0.06 4.42 0.65 0.74 0.00 0.23SEQID-00128 0.03 0.07 0.04 0.06 0.06 0.01 0.02 0.07 −16.81 0.57 0.049.31 0.25 0.30 0.23 0.25 SEQID-00129 0.03 0.06 0.04 0.03 0.04 0.02 0.040.11 −16.17 0.61 −0.01 6.63 0.24 0.30 0.00 0.28 SEQID-00130 0.02 0.070.03 0.03 0.05 0.05 0.02 0.07 −17.34 0.56 0.03 8.89 0.23 0.34 0.00 0.23SEQID-00131 0.03 0.03 0.04 0.03 0.04 0.02 0.03 0.05 −21.19 0.47 −0.035.04 0.96 0.99 0.22 0.24 SEQID-00132 0.00 0.05 0.02 0.03 0.02 0.03 0.030.05 −15.02 1.17 0.02 9.22 0.35 0.22 0.34 0.35 SEQID-00133 0.04 0.020.00 0.01 0.02 0.06 0.03 0.03 −23.93 1.02 0.04 9.95 0.33 0.21 0.00 0.35SEQID-00134 0.02 0.03 0.03 0.14 0.05 0.00 0.00 0.07 −10.60 1.38 −0.034.49 0.33 0.22 0.00 0.34 SEQID-00135 0.00 0.03 0.04 0.06 0.04 0.00 0.000.09 −15.04 0.70 −0.02 6.67 0.32 0.21 0.00 0.31 SEQID-00136 0.00 0.030.04 0.08 0.04 0.00 0.00 0.09 −16.20 0.65 0.00 7.09 0.31 0.20 0.00 0.29SEQID-00137 0.02 0.03 0.00 0.03 0.09 0.00 0.03 0.09 −18.91 0.89 −0.034.79 0.31 0.20 0.00 0.32 SEQID-00138 0.02 0.00 0.04 0.06 0.09 0.00 0.000.04 −14.32 0.74 −0.02 6.22 0.33 0.22 0.00 0.28 SEQID-00139 0.00 0.000.00 0.03 0.03 0.00 0.03 0.07 −31.57 0.29 −0.03 5.00 0.33 0.21 0.00 0.31SEQID-00140 0.02 0.10 0.03 0.08 0.07 0.03 0.00 0.09 −17.13 0.77 −0.017.52 0.31 0.20 0.31 0.28 SEQID-00141 0.02 0.05 0.05 0.01 0.03 0.03 0.050.05 −16.98 0.76 0.01 7.61 0.30 0.19 0.25 0.17 SEQID-00142 0.02 0.020.00 0.01 0.08 0.06 0.03 0.03 −20.09 0.24 0.08 10.05 0.32 0.21 0.29 0.30SEQID-00143 0.02 0.07 0.05 0.03 0.05 0.03 0.05 0.11 −19.93 0.52 0.028.49 0.33 0.22 0.32 0.32 SEQID-00144 0.04 0.15 0.02 0.01 0.07 0.03 0.030.07 −17.29 0.58 0.00 7.25 0.31 0.20 0.39 0.32 SEQID-00145 0.02 0.030.02 0.05 0.02 0.03 0.03 0.13 −16.57 0.79 −0.04 4.79 0.90 0.58 0.33 0.24SEQID-00146 0.02 0.10 0.03 0.08 0.09 0.03 0.00 0.07 −16.05 0.65 −0.016.50 0.32 0.20 0.28 0.31 SEQID-00147 0.03 0.03 0.03 0.07 0.06 0.02 0.030.12 −16.21 0.73 −0.03 4.70 0.24 0.23 0.00 0.23 SEQID-00148 0.00 0.010.05 0.02 0.01 0.05 0.00 0.11 −17.15 0.83 0.04 10.46 0.31 0.30 0.30 0.00SEQID-00149 0.02 0.01 0.04 0.05 0.06 0.00 0.00 0.09 −17.64 0.65 0.049.98 0.27 0.30 0.00 0.00 SEQID-00150 0.04 0.13 0.00 0.03 0.06 0.02 0.040.06 −21.64 0.55 −0.01 6.24 0.25 0.26 0.26 0.26 SEQID-00151 0.02 0.040.01 0.02 0.03 0.02 0.05 0.07 −24.45 0.54 0.09 10.51 0.29 0.32 0.24 0.25SEQID-00152 0.02 0.06 0.02 0.04 0.02 0.02 0.05 0.06 −23.71 0.37 0.039.12 0.26 0.30 0.27 0.29 SEQID-00153 0.02 0.03 0.03 0.05 0.05 0.02 0.030.06 −22.23 0.52 −0.06 4.38 0.72 0.74 0.00 0.19 SEQID-00154 0.03 0.080.03 0.05 0.02 0.03 0.03 0.09 −18.41 0.58 0.01 7.51 0.26 0.29 0.29 0.25SEQID-00155 0.03 0.02 0.05 0.01 0.04 0.05 0.11 0.07 −17.59 0.58 0.007.40 0.58 0.60 0.00 0.23 SEQID-00156 0.02 0.05 0.02 0.04 0.03 0.02 0.060.06 −22.73 0.51 0.04 9.19 0.23 0.29 0.26 0.26 SEQID-00157 0.04 0.040.03 0.05 0.05 0.01 0.06 0.07 −19.38 0.39 −0.02 5.62 0.31 0.44 0.00 0.21SEQID-00158 0.03 0.07 0.02 0.05 0.05 0.02 0.04 0.08 −19.98 0.57 −0.025.35 0.00 0.31 0.00 0.24 SEQID-00159 0.04 0.07 0.05 0.06 0.05 0.01 0.030.07 −17.02 0.48 −0.04 4.70 0.47 0.53 0.00 0.22 SEQID-00160 0.03 0.090.01 0.05 0.06 0.02 0.04 0.08 −19.43 0.57 −0.02 5.68 0.18 0.31 0.22 0.26SEQID-00161 0.03 0.03 0.04 0.06 0.09 0.01 0.06 0.10 −15.61 0.48 0.049.92 0.29 0.38 0.00 0.22 SEQID-00162 0.05 0.00 0.10 0.06 0.02 0.00 0.030.05 −6.47 1.39 −0.02 5.45 0.34 0.22 0.28 0.36 SEQID-00163 0.01 0.130.03 0.04 0.02 0.02 0.07 0.04 −11.56 1.34 0.03 9.43 0.22 0.27 0.00 0.23SEQID-00164 0.04 0.07 0.01 0.03 0.03 0.03 0.05 0.22 −5.03 1.99 0.02 9.170.29 0.22 0.00 0.34 SEQID-00165 0.02 0.00 0.03 0.07 0.08 0.06 0.03 0.17−4.16 1.81 0.00 6.41 0.30 0.23 0.27 0.00 SEQID-00166 0.03 0.05 0.07 0.020.08 0.00 0.03 0.08 −5.92 1.63 0.00 7.70 0.25 0.30 0.00 0.27 SEQID-001670.04 0.05 0.07 0.05 0.10 0.03 0.02 0.02 −6.50 1.19 0.02 10.10 0.21 0.330.00 0.24 SEQID-00168 0.05 0.04 0.06 0.05 0.10 0.03 0.02 0.03 −6.42 1.260.01 9.66 0.21 0.33 0.00 0.00 SEQID-00169 0.04 0.09 0.14 0.04 0.02 0.000.03 0.05 −5.08 1.18 −0.03 4.18 0.29 0.20 0.32 0.33 SEQID-00170 0.050.04 0.07 0.06 0.09 0.03 0.02 0.02 −6.50 1.19 0.02 9.72 0.21 0.33 0.000.00 SEQID-00171 0.04 0.06 0.07 0.03 0.09 0.04 0.03 0.05 −5.71 1.32 0.0210.04 0.23 0.31 0.00 0.22 SEQID-00172 0.09 0.06 0.01 0.05 0.07 0.00 0.050.07 −5.77 1.52 −0.01 6.20 0.26 0.28 0.00 0.24 SEQID-00173 0.05 0.070.07 0.03 0.09 0.04 0.03 0.05 −6.03 1.24 0.01 9.63 0.21 0.33 0.00 0.20SEQID-00174 0.04 0.08 0.08 0.03 0.10 0.06 0.01 0.04 −7.89 1.02 0.0210.42 0.23 0.32 0.00 0.26 SEQID-00175 0.04 0.11 0.02 0.00 0.05 0.03 0.080.05 −6.10 1.53 −0.05 3.93 0.29 0.21 0.00 0.26 SEQID-00176 0.06 0.080.05 0.06 0.10 0.02 0.01 0.05 −6.48 1.21 0.02 10.57 0.00 0.32 0.00 0.00SEQID-00177 0.02 0.11 0.01 0.07 0.06 0.03 0.06 0.09 −4.33 1.65 −0.015.45 0.00 0.30 0.22 0.27 SEQID-00178 0.05 0.14 0.04 0.04 0.03 0.02 0.060.05 −6.01 1.52 0.00 7.34 0.22 0.28 0.27 0.20 SEQID-00179 0.01 0.11 0.040.07 0.03 0.03 0.06 0.04 −9.40 1.40 −0.02 4.73 0.23 0.33 0.00 0.27SEQID-00180 0.06 0.05 0.07 0.05 0.07 0.08 0.04 0.02 −7.83 1.16 0.00 6.950.20 0.30 0.00 0.27 SEQID-00181 0.07 0.10 0.03 0.03 0.09 0.02 0.04 0.01−8.86 1.29 −0.01 5.65 0.29 0.32 0.00 0.23 SEQID-00182 0.05 0.08 0.050.06 0.04 0.05 0.06 0.04 −7.84 1.36 0.02 9.13 0.25 0.28 0.00 0.25SEQID-00183 0.02 0.10 0.02 0.03 0.08 0.02 0.04 0.03 −9.90 1.21 −0.044.17 0.18 0.28 0.23 0.27 SEQID-00184 0.04 0.16 0.02 0.05 0.03 0.05 0.070.06 −10.84 1.38 −0.04 4.29 0.27 0.28 0.27 0.23 SEQID-00185 0.02 0.110.03 0.08 0.03 0.05 0.06 0.04 −10.00 1.28 0.01 8.21 0.26 0.31 0.24 0.26SEQID-00186 0.05 0.14 0.02 0.03 0.05 0.04 0.04 0.07 −9.98 1.54 0.02 9.170.25 0.28 0.00 0.22 SEQID-00187 0.02 0.18 0.03 0.05 0.05 0.02 0.03 0.07−7.42 1.30 0.01 8.23 0.23 0.28 0.20 0.27 SEQID-00188 0.04 0.03 0.07 0.040.10 0.03 0.00 0.04 −6.18 1.52 0.00 7.72 0.25 0.33 0.00 0.26 SEQID-001890.07 0.04 0.08 0.05 0.11 0.07 0.01 0.01 −6.44 1.10 0.06 12.27 0.23 0.290.00 0.30 SEQID-00190 0.05 0.01 0.08 0.05 0.12 0.03 0.01 0.01 −5.82 1.110.01 9.35 0.27 0.30 0.24 0.27 SEQID-00191 0.05 0.01 0.09 0.05 0.12 0.020.01 0.02 −6.73 1.262 0.03 10.24 0.27 0.30 0.00 0.29 SEQID-00192 0.040.00 0.07 0.05 0.12 0.00 0.00 0.03 −6.30 1.37 0.00 7.72 0.23 0.27 0.000.29 SEQID-00193 0.02 0.03 0.03 0.08 0.04 0.00 0.00 0.04 −18.69 0.540.02 9.44 0.29 0.18 0.24 0.35 SEQID-00194 0.02 0.03 0.03 0.08 0.04 0.000.00 0.04 −17.31 0.54 0.04 10.49 0.31 0.20 0.24 0.33 SEQID-00195 0.020.00 0.03 0.09 0.04 0.00 0.00 0.04 −17.40 0.47 0.04 10.49 0.31 0.20 0.220.34 SEQID-00196 0.03 0.04 0.03 0.06 0.04 0.00 0.02 0.04 −22.65 0.390.00 7.42 0.24 0.32 0.25 0.25 SEQID-00197 0.03 0.04 0.03 0.06 0.04 0.000.02 0.04 −22.50 0.39 0.00 7.42 0.20 0.32 0.25 0.25 SEQID-00198 0.030.04 0.03 0.06 0.04 0.00 0.02 0.04 −22.35 0.39 0.00 7.42 0.00 0.32 0.250.26 SEQID-00199 0.03 0.04 0.03 0.06 0.04 0.00 0.02 0.04 −22.74 0.390.00 6.53 0.23 0.32 0.00 0.25 SEQID-00200 0.03 0.04 0.03 0.06 0.04 0.000.02 0.04 −22.59 0.39 0.00 6.53 0.23 0.32 0.00 0.25 SEQID-00201 0.030.04 0.03 0.06 0.04 0.00 0.02 0.04 −22.97 0.38 −0.01 5.82 0.22 0.32 0.240.25 SEQID-00202 0.03 0.04 0.03 0.06 0.04 0.00 0.02 0.04 −23.34 0.38−0.02 5.32 0.22 0.32 0.24 0.25 SEQID-00203 0.03 0.04 0.03 0.05 0.04 0.000.02 0.04 −23.25 0.38 −0.02 5.32 0.22 0.32 0.24 0.25 SEQID-00204 0.030.04 0.03 0.05 0.04 0.00 0.02 0.04 −23.61 0.37 −0.02 5.06 0.25 0.32 0.000.25 SEQID-00205 0.03 0.04 0.04 0.06 0.04 0.00 0.02 0.04 −24.11 0.36−0.04 4.67 0.25 0.32 0.23 0.26 SEQID-00206 0.00 0.02 0.02 0.00 0.03 0.090.03 0.08 −27.16 0.30 0.10 10.48 0.32 0.10 0.29 0.25 SEQID-00207 0.020.02 0.01 0.00 0.04 0.07 0.02 0.06 −33.49 0.15 0.01 7.70 0.31 0.26 0.260.00 SEQID-00208 0.02 0.02 0.00 0.00 0.03 0.00 0.00 0.03 −37.87 0.120.18 4.11 0.34 0.23 0.29 0.27 SEQID-00209 0.01 0.04 0.01 0.01 0.03 0.040.01 0.05 −29.13 0.21 0.02 9.15 0.30 0.31 0.00 0.00 SEQID-00210 0.020.02 0.01 0.00 0.03 0.05 0.01 0.04 −32.93 0.17 −0.04 5.09 0.30 0.34 0.250.23 SEQID-00211 0.02 0.02 0.01 0.01 0.03 0.04 0.01 0.04 −33.59 0.15−0.05 4.95 0.30 0.34 0.25 0.00 SEQID-00212 0.00 0.00 0.00 0.01 0.03 0.000.03 0.05 −36.26 0.21 −0.06 4.77 0.34 0.21 0.29 0.33 SEQID-00213 0.000.00 0.00 0.01 0.05 0.00 0.03 0.05 −34.27 0.27 −0.04 4.76 0.35 0.22 0.250.00 SEQID-00214 0.00 0.00 0.00 0.01 0.06 0.00 0.02 0.05 −32.73 0.22−0.04 4.66 0.29 0.25 0.31 0.00 SEQID-00215 0.00 0.00 0.00 0.03 0.03 0.000.02 0.06 −34.50 0.23 0.00 7.54 0.31 0.21 0.00 0.00 SEQID-00216 0.000.02 0.00 0.02 0.03 0.00 0.02 0.05 −34.08 0.25 0.00 7.54 0.32 0.26 0.000.00 SEQID-00217 0.00 0.00 0.00 0.01 0.05 0.00 0.03 0.06 −35.54 0.25−0.09 4.33 0.34 0.23 0.00 0.00 SEQID-00218 0.00 0.00 0.00 0.01 0.05 0.000.03 0.05 −34.67 0.22 −0.07 4.60 0.34 0.23 0.25 0.00 SEQID-00219 0.000.00 0.00 0.03 0.03 0.00 0.03 0.07 −33.39 0.29 −0.02 5.81 0.32 0.20 0.000.31 SEQID-00220 0.00 0.00 0.00 0.01 0.05 0.00 0.02 0.05 −37.57 0.19−0.07 4.55 0.31 0.25 0.31 0.00 SEQID-00221 0.00 0.00 0.00 0.02 0.03 0.000.02 0.06 −35.42 0.21 −0.01 5.88 0.32 0.24 0.21 0.00 SEQID-00222 0.000.03 0.00 0.03 0.05 0.00 0.00 0.02 −30.85 0.13 −0.10 4.23 0.36 0.23 0.000.33 SEQID-00223 0.00 0.02 0.00 0.01 0.03 0.00 0.03 0.03 −33.68 0.26−0.02 5.81 0.36 0.23 0.00 0.00 SEQID-00224 0.00 0.00 0.00 0.01 0.06 0.000.02 0.06 −37.47 0.23 −0.05 4.66 0.33 0.25 0.00 0.00 SEQID-00225 0.000.01 0.00 0.02 0.04 0.00 0.01 0.04 −33.38 0.20 −0.02 5.31 0.30 0.31 0.000.00 SEQID-00226 0.00 0.01 0.00 0.02 0.04 0.00 0.01 0.04 −32.78 0.18−0.03 5.01 0.30 0.33 0.27 0.29 SEQID-00227 0.00 0.01 0.00 0.02 0.03 0.000.03 0.04 −36.89 0.16 −0.03 5.07 0.33 0.35 0.00 0.00 SEQID-00228 0.000.01 0.00 0.02 0.04 0.00 0.02 0.04 −37.66 0.15 −0.03 4.97 0.33 0.39 0.000.00 SEQID-00229 0.02 0.02 0.00 0.03 0.07 0.00 0.00 0.02 −32.91 0.12−0.10 4.28 0.38 0.25 0.00 0.00 SEQID-00230 0.00 0.03 0.00 0.03 0.02 0.000.00 0.02 −29.21 0.16 0.02 9.18 0.39 0.25 0.00 0.27 SEQID-00231 0.010.03 0.00 0.04 0.05 0.00 0.00 0.02 −28.20 0.17 −0.03 4.75 0.30 0.31 0.000.00 SEQID-00232 0.00 0.03 0.00 0.03 0.05 0.00 0.00 0.03 −30.24 0.120.04 10.27 0.31 0.33 0.00 0.00 SEQID-00233 0.00 0.06 0.02 0.07 0.05 0.000.00 0.08 −16.02 0.94 −0.06 4.03 0.26 0.32 0.00 1.00 SEQID-00234 0.000.07 0.02 0.07 0.04 0.00 0.00 0.08 −16.69 0.94 −0.07 4.03 0.23 0.30 0.001.00 SEQID-00235 0.00 0.07 0.01 0.08 0.04 0.00 0.03 0.06 −17.69 0.65−0.06 4.15 0.26 0.31 0.00 1.00 SEQID-00236 0.02 0.00 0.00 0.01 0.05 0.000.00 0.03 −34.37 0.07 −0.06 4.67 0.36 0.29 0.00 0.00 SEQID-00237 0.020.00 0.00 0.01 0.05 0.00 0.00 0.03 −38.56 0.08 −0.02 5.12 0.38 0.24 0.000.00 SEQID-00238 0.02 0.00 0.00 0.01 0.03 0.00 0.00 0.03 −38.44 0.16−0.09 4.53 0.35 0.24 0.27 0.32 SEQID-00239 0.06 0.02 0.00 0.01 0.02 0.000.00 0.00 −41.59 0.04 −0.02 5.16 0.42 0.26 0.00 0.00 SEQID-00240 0.040.00 0.00 0.03 0.02 0.00 0.00 0.00 −40.29 0.04 −0.04 4.82 0.37 0.23 0.280.00 SEQID-00241 0.02 0.00 0.00 0.01 0.07 0.00 0.00 0.03 −35.70 0.11−0.05 4.83 0.31 0.36 0.26 0.22 SEQID-00242 0.00 0.10 0.05 0.03 0.05 0.070.00 0.03 −5.77 1.91 −0.02 4.18 0.33 0.20 0.29 0.00 SEQID-00243 0.000.11 0.05 0.03 0.05 0.03 0.06 0.02 −4.36 1.69 0.00 6.23 0.31 0.19 0.000.33 SEQID-00244 0.05 0.00 0.04 0.11 0.15 0.03 0.00 0.00 −3.56 1.26 0.029.70 0.37 0.24 0.27 0.29 SEQID-00245 0.02 0.08 0.07 0.08 0.12 0.03 0.000.03 −5.24 1.22 0.00 7.55 0.30 0.19 0.00 0.36 SEQID-00246 0.00 0.08 0.020.03 0.04 0.03 0.00 0.05 −6.47 1.61 −0.05 3.87 0.29 0.19 0.00 0.29SEQID-00247 0.04 0.04 0.04 0.06 0.04 0.02 0.03 0.06 −7.06 1.30 −0.016.50 0.26 0.31 0.00 0.26 SEQID-00248 0.07 0.03 0.12 0.03 0.09 0.03 0.000.00 −6.58 1.34 0.00 6.49 0.33 0.22 0.00 0.29 SEQID-00249 0.07 0.04 0.090.02 0.06 0.02 0.00 0.02 −8.69 1.28 0.02 10.33 0.24 0.29 0.00 0.26SEQID-00250 0.00 0.00 0.05 0.02 0.09 0.07 0.03 0.04 −9.82 1.06 −0.054.57 0.33 0.21 0.00 0.37 SEQID-00251 0.03 0.04 0.03 0.06 0.09 0.02 0.040.04 −11.82 1.17 0.05 10.32 0.28 0.23 0.29 0.27 SEQID-00252 0.00 0.000.02 0.00 0.07 0.03 0.06 0.05 −14.21 1.06 0.05 10.00 0.31 0.20 0.36 0.30SEQID-00253 0.01 0.06 0.04 0.03 0.04 0.04 0.06 0.09 −10.95 1.37 0.028.24 0.25 0.27 0.27 0.28 SEQID-00254 0.01 0.05 0.04 0.03 0.04 0.02 0.070.09 −11.95 1.26 0.02 8.49 0.28 0.29 0.00 0.31 SEQID-00255 0.00 0.080.09 0.05 0.04 0.03 0.00 0.05 −7.56 1.49 0.05 10.79 0.36 0.23 0.35 0.31SEQID-00256 0.02 0.08 0.07 0.03 0.04 0.03 0.00 0.07 −8.27 1.48 0.02 9.540.33 0.22 0.36 0.33 SEQID-00257 0.07 0.05 0.06 0.03 0.10 0.06 0.03 0.03−3.63 1.30 0.02 9.30 0.35 0.24 0.00 0.00 SEQID-00258 0.09 0.02 0.03 0.040.03 0.03 0.00 0.03 −17.37 0.94 0.23 13.28 0.30 0.19 0.00 0.27SEQID-00259 0.00 0.05 0.02 0.05 0.06 0.00 0.00 0.02 −19.14 0.66 0.007.36 0.33 0.21 0.00 0.39 SEQID-00260 0.02 0.08 0.04 0.03 0.08 0.00 0.000.07 −10.46 1.44 0.00 7.25 0.30 0.19 0.23 0.34 SEQID-00261 0.00 0.100.03 0.04 0.07 0.00 0.03 0.03 −11.32 1.17 −0.03 4.54 0.31 0.20 0.00 0.29SEQID-00262 0.00 0.07 0.02 0.07 0.06 0.00 0.03 0.03 −17.75 0.73 −0.016.51 0.31 0.21 0.27 0.22 SEQID-00263 0.04 0.07 0.03 0.04 0.07 0.00 0.140.05 −5.22 1.51 0.00 7.24 0.37 0.24 0.00 0.29 SEQID-00264 0.02 0.01 0.000.02 0.05 0.00 0.00 0.02 −37.24 0.08 −0.07 4.58 0.29 0.37 0.22 0.00SEQID-00265 0.01 0.01 0.00 0.04 0.03 0.00 0.01 0.03 −34.97 0.13 −0.064.60 0.29 0.40 0.23 0.22 SEQID-00266 0.00 0.00 0.00 0.01 0.05 0.00 0.020.03 −37.57 0.18 −0.07 4.55 0.31 0.25 0.32 0.00 SEQID-00267 0.00 0.000.00 0.01 0.05 0.00 0.02 0.01 −37.57 0.17 −0.07 4.55 0.33 0.27 0.32 0.00SEQID-00268 0.00 0.00 0.00 0.01 0.05 0.00 0.02 0.00 −36.50 0.23 −0.094.42 0.35 0.28 0.33 0.00 SEQID-00269 0.00 0.00 0.00 0.01 0.04 0.00 0.020.00 −36.42 0.23 −0.09 4.42 0.34 0.27 0.00 0.00 SEQID-00270 0.00 0.000.00 0.01 0.04 0.00 0.02 0.00 −36.42 0.28 −0.09 4.42 0.38 0.31 0.00 0.26SEQID-00271 0.00 0.00 0.00 0.01 0.03 0.00 0.02 0.00 −36.19 0.40 −0.094.42 0.35 0.29 0.00 0.00 SEQID-00272 0.00 0.00 0.00 0.01 0.05 0.00 0.020.00 −37.57 0.19 −0.07 4.55 0.33 0.27 0.33 0.00 SEQID-00273 0.00 0.000.00 0.01 0.05 0.00 0.02 0.00 −37.42 0.26 −0.07 4.55 0.35 0.28 0.00 0.00SEQID-00274 0.00 0.00 0.00 0.01 0.04 0.00 0.02 0.00 −37.34 0.37 −0.074.55 0.35 0.28 0.00 0.00 SEQID-00275 0.00 0.00 0.00 0.01 0.03 0.00 0.020.00 −37.26 0.37 −0.07 4.55 0.34 0.28 0.36 0.00 SEQID-00276 0.00 0.000.00 0.00 0.04 0.00 0.00 0.00 −37.16 0.47 −0.07 4.55 0.35 0.29 0.00 0.00SEQID-00277 0.03 0.06 0.02 0.06 0.09 0.02 0.05 0.11 −13.06 1.31 0.079.64 0.23 0.29 0.22 0.25 SEQID-00278 0.02 0.08 0.06 0.05 0.06 0.05 0.110.07 −18.57 0.24 −0.01 5.38 0.25 0.38 0.20 0.21 SEQID-00279 0.00 0.000.00 0.01 0.04 0.00 0.02 0.00 −36.27 0.40 −0.09 4.42 0.35 0.29 0.00 0.00SEQID-00280 0.00 0.00 0.00 0.01 0.03 0.00 0.02 0.00 −37.26 0.37 −0.074.55 0.35 0.28 0.00 0.00 SEQID-00281 0.02 0.05 0.03 0.03 0.05 0.05 0.060.08 −19.78 0.35 −0.03 5.12 0.21 0.33 0.00 0.20 SEQID-00282 0.04 0.100.00 0.03 0.07 0.06 0.00 0.10 −19.86 1.03 0.09 9.58 0.44 0.14 0.42 0.38SEQID-00283 0.02 0.05 0.03 0.01 0.05 0.03 0.05 0.08 −26.91 0.45 0.1210.39 0.28 0.18 0.30 0.22 SEQID-00284 0.04 0.04 0.04 0.04 0.05 0.01 0.040.08 −25.52 0.46 0.01 7.51 0.23 0.29 0.00 0.25 SEQID-00285 0.04 0.060.01 0.01 0.07 0.03 0.02 0.08 −25.31 0.52 0.09 10.56 0.31 0.23 0.00 0.00SEQID-00286 0.04 0.05 0.00 0.03 0.06 0.03 0.05 0.09 −20.36 0.77 0.069.29 0.34 0.23 0.31 0.22 SEQID-00287 0.02 0.05 0.00 0.04 0.06 0.02 0.040.08 −23.00 0.80 −0.02 5.64 0.29 0.27 0.00 0.24 SEQID-00288 0.03 0.030.03 0.06 0.05 0.04 0.04 0.07 −21.14 0.53 0.01 7.38 0.20 0.33 0.19 0.17SEQID-00289 0.04 0.07 0.02 0.06 0.06 0.06 0.03 0.08 −20.21 0.69 0.017.63 0.23 0.33 0.00 0.22 SEQID-00290 0.04 0.04 0.05 0.05 0.04 0.01 0.040.08 −19.04 0.52 0.00 6.72 0.21 0.32 0.00 0.19 SEQID-00291 0.01 0.070.02 0.05 0.05 0.04 0.03 0.08 −20.82 0.80 −0.02 5.66 0.23 0.27 0.00 0.25SEQID-00292 0.02 0.05 0.00 0.04 0.06 0.02 0.04 0.07 −23.98 0.70 −0.025.64 0.29 0.25 0.27 0.25 SEQID-00293 0.02 0.05 0.01 0.04 0.07 0.02 0.040.08 −22.45 0.79 −0.02 5.64 0.28 0.27 0.27 0.25 SEQID-00294 0.02 0.070.01 0.04 0.06 0.02 0.04 0.08 −22.10 0.80 −0.02 5.64 0.28 0.27 0.28 0.24SEQID-00295 0.02 0.05 0.00 0.04 0.07 0.02 0.04 0.07 −22.75 0.77 −0.025.64 0.30 0.28 0.31 0.25 SEQID-00296 0.02 0.05 0.00 0.05 0.07 0.02 0.040.07 −23.28 0.71 −0.03 5.00 0.29 0.28 0.28 0.25 SEQID-00297 0.03 0.060.02 0.03 0.03 0.02 0.02 0.05 −22.84 0.36 0.01 7.50 0.24 0.30 0.23 0.24SEQID-00298 0.03 0.06 0.02 0.03 0.03 0.02 0.02 0.05 −22.93 0.37 0.017.54 0.29 0.30 0.23 0.22 SEQID-00299 0.03 0.06 0.02 0.04 0.03 0.02 0.020.05 −23.45 0.34 0.01 7.38 0.24 0.31 0.21 0.23 SEQID-00300 0.02 0.070.04 0.03 0.03 0.02 0.05 0.06 −29.09 0.40 −0.18 3.78 0.22 0.31 0.00 0.23SEQID-00301 0.03 0.07 0.04 0.03 0.03 0.02 0.05 0.07 −28.15 0.40 −0.173.78 0.22 0.31 0.00 0.21 SEQID-00302 0.02 0.05 0.03 0.06 0.05 0.01 0.020.08 −19.36 0.48 −0.03 4.71 0.23 0.33 0.21 0.22 SEQID-00303 0.03 0.060.04 0.05 0.05 0.02 0.06 0.05 −19.91 0.43 −0.03 5.01 0.20 0.31 0.00 0.23SEQID-00304 0.03 0.04 0.04 0.03 0.04 0.01 0.08 0.07 −23.25 0.38 −0.035.16 0.21 0.32 0.00 0.18 SEQID-00305 0.01 0.03 0.05 0.04 0.05 0.01 0.050.05 −18.71 0.40 0.02 8.31 0.20 0.33 0.00 0.21 SEQID-00306 0.04 0.050.04 0.05 0.04 0.02 0.02 0.09 −20.25 0.45 0.01 8.46 0.23 0.33 0.21 0.23SEQID-00307 0.02 0.05 0.03 0.05 0.08 0.02 0.04 0.04 −20.51 0.44 0.029.38 0.00 0.31 0.00 0.21 SEQID-00308 0.02 0.04 0.04 0.07 0.06 0.02 0.040.05 −20.65 0.37 0.00 7.10 0.22 0.33 0.22 0.22 SEQID-00309 0.02 0.020.05 0.06 0.05 0.05 0.07 0.04 −21.70 0.29 −0.04 4.85 0.23 0.33 0.20 0.20SEQID-00310 0.05 0.09 0.04 0.03 0.04 0.03 0.05 0.06 −20.85 0.36 0.007.29 0.23 0.32 0.24 0.25 SEQID-00311 0.03 0.08 0.04 0.03 0.04 0.03 0.070.05 −19.63 0.26 0.05 9.70 0.21 0.30 0.25 0.23 SEQID-00312 0.04 0.030.03 0.07 0.06 0.01 0.05 0.07 −20.18 0.48 −0.06 4.54 0.00 0.30 0.00 0.00SEQID-00313 0.03 0.03 0.04 0.08 0.06 0.02 0.04 0.07 −20.16 0.44 −0.025.53 0.21 0.34 0.22 0.22 SEQID-00314 0.06 0.05 0.02 0.05 0.07 0.01 0.040.04 −23.28 0.41 0.05 10.12 0.21 0.33 0.16 0.19 SEQID-00315 0.03 0.060.03 0.04 0.05 0.02 0.06 0.04 −21.95 0.32 −0.04 4.83 0.18 0.31 0.00 0.13SEQID-00316 0.03 0.07 0.04 0.05 0.06 0.02 0.04 0.03 −20.35 0.36 0.028.34 0.21 0.33 0.19 0.20 SEQID-00317 0.03 0.05 0.02 0.08 0.08 0.01 0.040.05 −20.14 0.25 −0.02 4.83 0.21 0.34 0.00 0.21 SEQID-00318 0.02 0.060.04 0.06 0.05 0.05 0.08 0.04 −17.30 0.36 −0.01 6.18 0.00 0.33 0.00 0.20SEQID-00319 0.03 0.05 0.03 0.04 0.05 0.04 0.07 0.06 −19.59 0.36 −0.026.07 0.20 0.34 0.00 0.20 SEQID-00320 0.03 0.06 0.02 0.03 0.03 0.02 0.070.04 −28.07 0.20 −0.01 6.59 0.23 0.34 0.22 0.21 SEQID-00321 0.04 0.040.02 0.05 0.03 0.01 0.07 0.06 −22.70 0.40 0.03 9.29 0.23 0.33 0.00 0.00SEQID-00322 0.03 0.03 0.03 0.05 0.06 0.04 0.07 0.06 −19.27 0.31 −0.016.37 0.22 0.34 0.22 0.21 SEQID-00323 0.01 0.06 0.04 0.06 0.04 0.03 0.070.04 −21.48 0.31 0.04 9.36 0.00 0.33 0.00 0.00 SEQID-00324 0.03 0.090.04 0.06 0.04 0.03 0.09 0.03 −20.93 0.27 −0.01 6.45 0.16 0.33 0.00 0.19SEQID-00325 0.02 0.03 0.04 0.03 0.05 0.01 0.14 0.05 −22.26 0.22 0.049.39 0.23 0.30 0.21 0.00 SEQID-00326 0.03 0.07 0.05 0.05 0.05 0.03 0.070.05 −19.44 0.37 −0.01 6.51 0.26 0.30 0.24 0.23 SEQID-00327 0.03 0.060.02 0.08 0.03 0.01 0.04 0.06 −22.60 0.39 0.00 6.53 0.26 0.29 0.30 0.00SEQID-00328 0.05 0.04 0.01 0.03 0.02 0.01 0.02 0.05 −26.69 0.22 0.2112.35 0.25 0.29 0.24 0.23 SEQID-00329 0.02 0.01 0.03 0.06 0.05 0.01 0.030.12 −26.66 0.27 0.18 11.94 0.24 0.28 0.20 0.25 SEQID-00330 0.02 0.030.01 0.02 0.06 0.02 0.04 0.06 −24.07 0.28 0.09 10.90 0.23 0.29 0.00 0.21SEQID-00331 0.03 0.04 0.02 0.07 0.08 0.04 0.07 0.04 −19.13 0.41 0.049.73 0.23 0.30 0.24 0.27 SEQID-00332 0.03 0.03 0.02 0.05 0.08 0.02 0.060.04 −21.07 0.28 −0.04 4.72 0.22 0.34 0.00 0.20 SEQID-00333 0.02 0.070.01 0.03 0.03 0.04 0.08 0.05 −19.36 0.44 0.05 9.83 0.18 0.31 0.28 0.22SEQID-00334 0.02 0.05 0.03 0.03 0.03 0.01 0.05 0.06 −26.57 0.28 0.1010.98 0.00 0.33 0.00 0.20 SEQID-00335 0.03 0.01 0.04 0.04 0.03 0.01 0.070.07 −21.68 0.28 0.10 11.31 0.22 0.30 0.00 0.26 SEQID-00336 0.05 0.020.04 0.05 0.02 0.02 0.03 0.05 −29.65 0.18 0.22 12.00 0.24 0.32 0.18 0.23SEQID-00337 0.01 0.08 0.05 0.02 0.05 0.01 0.06 0.06 −20.90 0.36 0.006.86 0.19 0.34 0.00 0.00 SEQID-00338 0.04 0.03 0.05 0.04 0.05 0.02 0.020.04 −21.97 0.28 −0.01 6.37 0.00 0.35 0.25 0.00 SEQID-00339 0.02 0.020.03 0.03 0.04 0.04 0.06 0.05 −25.07 0.25 −0.03 5.57 0.19 0.30 0.21 0.00SEQID-00340 0.00 0.02 0.03 0.04 0.05 0.02 0.04 0.07 −22.52 0.30 0.0510.51 0.21 0.31 0.00 0.00 SEQID-00341 0.03 0.02 0.03 0.09 0.05 0.01 0.070.04 −23.40 0.28 −0.06 4.54 0.21 0.33 0.00 0.20 SEQID-00342 0.04 0.070.03 0.05 0.06 0.03 0.04 0.03 −20.62 0.33 0.02 9.39 0.21 0.32 0.00 0.21SEQID-00343 0.01 0.03 0.01 0.04 0.04 0.01 0.06 0.06 −26.83 0.38 0.028.41 0.24 0.31 0.00 0.00 SEQID-00344 0.01 0.02 0.06 0.07 0.05 0.02 0.040.07 −16.90 0.50 0.03 10.12 0.22 0.31 0.00 0.00 SEQID-00345 0.02 0.050.05 0.02 0.04 0.02 0.06 0.06 −18.75 0.39 −0.02 5.68 0.20 0.34 0.19 0.00SEQID-00346 0.03 0.05 0.03 0.03 0.05 0.01 0.06 0.07 −19.87 0.46 −0.025.27 0.21 0.31 0.00 0.00 SEQID-00347 0.03 0.04 0.03 0.08 0.08 0.01 0.050.05 −21.72 0.35 −0.01 6.27 0.23 0.33 0.00 0.23 SEQID-00348 0.04 0.020.03 0.06 0.05 0.03 0.02 0.12 −18.43 0.59 0.01 7.75 0.24 0.33 0.21 0.22SEQID-00349 0.02 0.05 0.03 0.04 0.05 0.02 0.08 0.06 −21.95 0.32 −0.026.35 0.20 0.31 0.00 0.21 SEQID-00350 0.02 0.05 0.05 0.06 0.03 0.00 0.030.05 −18.20 0.43 0.02 8.65 0.00 0.32 0.00 0.23 SEQID-00351 0.02 0.050.04 0.06 0.06 0.01 0.03 0.09 −19.26 0.50 −0.01 6.19 0.23 0.34 0.00 0.22SEQID-00352 0.02 0.05 0.04 0.04 0.06 0.01 0.03 0.09 −30.47 0.53 −0.015.58 0.23 0.33 0.00 0.21 SEQID-00353 0.03 0.05 0.06 0.06 0.03 0.02 0.080.07 −17.60 0.45 −0.03 4.69 0.21 0.32 0.00 0.20 SEQID-00354 0.04 0.050.04 0.05 0.04 0.02 0.02 0.09 −20.25 0.45 0.01 8.46 0.23 0.33 0.21 0.23SEQID-00355 0.02 0.07 0.05 0.08 0.07 0.01 0.02 0.06 −17.37 0.50 0.006.65 0.21 0.35 0.00 1.00 SEQID-00356 0.01 0.05 0.05 0.05 0.04 0.01 0.030.09 −19.88 0.46 −0.02 4.98 0.21 0.33 0.00 0.22 SEQID-00357 0.03 0.020.05 0.05 0.04 0.01 0.03 0.06 −18.65 0.48 −0.02 5.37 0.21 0.34 0.21 0.21SEQID-00358 0.04 0.07 0.04 0.03 0.06 0.03 0.04 0.05 −20.25 0.37 −0.016.46 0.20 0.35 0.20 0.21 SEQID-00359 0.03 0.02 0.04 0.05 0.04 0.01 0.030.06 −22.70 0.38 0.01 9.34 0.21 0.34 0.21 0.21 SEQID-00360 0.03 0.060.05 0.04 0.03 0.04 0.07 0.06 −19.19 0.37 −0.02 5.22 0.21 0.33 0.21 0.22SEQID-00361 0.03 0.06 0.04 0.04 0.04 0.00 0.04 0.07 −22.15 0.34 0.006.94 0.21 0.31 0.00 0.21 SEQID-00362 0.03 0.07 0.05 0.05 0.04 0.02 0.060.06 −23.27 0.34 −0.01 6.22 0.21 0.33 0.19 0.22 SEQID-00363 0.00 0.050.03 0.11 0.11 0.05 0.07 0.06 −15.13 0.40 −0.06 3.96 0.21 0.38 0.00 0.21SEQID-00364 0.03 0.02 0.07 0.01 0.02 0.04 0.14 0.03 −45.75 0.03 −0.244.02 0.30 0.28 0.28 0.29 SEQID-00365 0.01 0.03 0.04 0.03 0.03 0.15 0.050.03 −24.44 0.13 0.04 8.21 0.26 0.27 0.28 0.27 SEQID-00366 0.00 0.140.07 0.06 0.05 0.13 0.04 0.01 −22.70 0.11 0.04 10.10 0.27 0.24 0.00 0.27SEQID-00367 0.02 0.02 0.04 0.05 0.05 0.00 0.22 0.01 −27.90 0.00 −0.173.77 0.30 0.27 0.28 0.26 SEQID-00368 0.03 0.05 0.01 0.04 0.04 0.02 0.020.02 −26.53 0.31 −0.04 4.88 0.23 0.26 0.00 0.21 SEQID-00369 0.02 0.000.00 0.03 0.06 0.00 0.00 0.03 −22.97 0.22 0.01 7.80 0.35 0.30 0.00 0.00SEQID-00370 0.02 0.02 0.00 0.01 0.04 0.00 0.00 0.02 −25.72 0.17 −0.084.31 0.34 0.31 0.00 0.32 SEQID-00371 0.01 0.01 0.00 0.02 0.03 0.02 0.030.03 −32.01 0.12 −0.15 4.19 0.34 0.34 0.00 0.25 SEQID-00372 0.03 0.050.01 0.02 0.02 0.02 0.06 0.04 −24.83 0.16 −0.01 5.83 0.27 0.23 0.00 0.00SEQID-00373 0.01 0.05 0.04 0.09 0.02 0.02 0.04 0.03 −23.94 0.21 −0.025.07 0.27 0.26 0.00 0.29 SEQID-00374 0.03 0.06 0.01 0.03 0.03 0.04 0.030.08 −25.39 0.30 0.05 10.23 0.25 0.27 0.00 0.24 SEQID-00375 0.03 0.040.04 0.03 0.02 0.02 0.06 0.07 −28.50 0.25 0.14 11.20 0.31 0.26 0.00 0.21SEQID-00376 0.01 0.02 0.04 0.02 0.05 0.01 0.01 0.09 −24.79 0.46 0.1111.40 0.26 0.31 0.27 0.23 SEQID-00377 0.00 0.02 0.00 0.05 0.09 0.01 0.000.04 −24.99 0.04 −0.13 3.98 0.27 0.35 0.22 0.00 SEQID-00378 0.02 0.010.02 0.06 0.05 0.01 0.02 0.03 −25.00 0.15 −0.07 4.35 0.24 0.33 0.00 0.25SEQID-00379 0.01 0.01 0.00 0.02 0.03 0.02 0.00 0.05 −25.41 0.18 −0.026.12 0.29 0.35 0.24 0.27 SEQID-00380 0.02 0.02 0.00 0.06 0.04 0.02 0.000.02 −28.46 0.17 −0.05 4.69 0.35 0.33 0.00 0.23 SEQID-00381 0.02 0.010.02 0.03 0.02 0.01 0.02 0.04 −30.97 0.39 0.05 9.63 0.29 0.34 0.24 0.25SEQID-00382 0.03 0.02 0.04 0.04 0.01 0.02 0.00 0.08 −33.88 0.23 0.1411.31 0.33 0.29 0.30 0.21 SEQID-00383 0.02 0.03 0.02 0.01 0.01 0.02 0.080.02 −29.58 0.21 0.10 10.66 0.25 0.22 0.24 0.00 SEQID-00384 0.02 0.050.01 0.02 0.09 0.02 0.04 0.05 −25.11 0.31 0.12 11.78 0.23 0.30 0.00 0.00SEQID-00385 0.03 0.02 0.03 0.05 0.08 0.00 0.00 0.13 −26.46 0.42 0.0711.42 0.29 0.24 0.00 0.00 SEQID-00386 0.02 0.00 0.04 0.14 0.04 0.03 0.010.06 −19.07 0.39 −0.03 4.51 0.24 0.30 0.00 0.24 SEQID-00387 0.03 0.010.05 0.06 0.04 0.02 0.01 0.11 −23.24 0.49 0.02 9.25 0.00 0.30 0.00 0.23SEQID-00388 0.03 0.01 0.05 0.06 0.04 0.02 0.00 0.11 −23.34 0.50 0.029.30 0.25 0.30 0.00 0.24 SEQID-00389 0.03 0.01 0.05 0.04 0.03 0.00 0.030.11 −21.13 0.37 0.09 10.92 0.21 0.33 0.00 0.25 SEQID-00390 0.02 0.030.03 0.05 0.07 0.02 0.05 0.04 −21.63 0.38 0.01 9.14 0.00 0.30 0.00 0.00SEQID-00391 0.03 0.02 0.04 0.08 0.06 0.02 0.04 0.06 −20.87 0.38 −0.025.05 0.22 0.34 0.22 0.22 SEQID-00392 0.02 0.06 0.03 0.04 0.05 0.02 0.060.04 −22.88 0.23 −0.04 4.76 0.18 0.31 0.00 0.00 SEQID-00393 0.03 0.070.04 0.06 0.06 0.02 0.04 0.03 −19.96 0.35 0.01 8.65 0.21 0.33 0.00 0.21SEQID-00394 0.02 0.05 0.04 0.06 0.06 0.05 0.09 0.04 −17.65 0.27 −0.025.57 0.19 0.33 0.00 0.00 SEQID-00395 0.02 0.05 0.06 0.06 0.03 0.02 0.080.06 −18.60 0.38 −0.04 4.52 0.21 0.32 0.00 0.21 SEQID-00396 0.01 0.040.00 0.05 0.06 0.02 0.07 0.04 −25.26 0.21 0.01 8.44 0.17 0.30 0.00 0.00SEQID-00397 0.01 0.04 0.06 0.06 0.05 0.04 0.04 0.04 −20.27 0.20 0.0610.19 0.21 0.31 0.00 0.21 SEQID-00398 0.04 0.03 0.04 0.04 0.05 0.02 0.070.06 −21.47 0.27 0.01 8.63 0.22 0.32 0.00 0.00 SEQID-00399 0.02 0.030.04 0.05 0.04 0.02 0.07 0.06 −25.17 0.29 −0.05 4.89 0.20 0.34 0.00 0.20SEQID-00400 0.03 0.06 0.01 0.05 0.07 0.04 0.05 0.06 −23.79 0.29 −0.016.64 0.23 0.30 0.00 0.00 SEQID-00401 0.01 0.05 0.04 0.05 0.10 0.01 0.040.08 −18.97 0.39 −0.01 5.14 0.27 0.31 0.00 0.28 SEQID-00402 0.01 0.030.02 0.07 0.06 0.02 0.04 0.06 −25.96 0.30 0.00 7.19 0.21 0.32 0.00 0.00SEQID-00403 0.02 0.04 0.04 0.07 0.05 0.02 0.05 0.05 −21.38 0.33 0.006.70 0.22 0.33 0.00 0.22 SEQID-00404 0.02 0.06 0.04 0.07 0.14 0.01 0.030.02 −16.05 0.35 0.03 9.57 0.21 0.30 0.18 0.25 SEQID-00405 0.02 0.030.04 0.10 0.06 0.03 0.10 0.03 −15.43 0.25 0.00 6.53 0.19 0.33 0.00 0.21SEQID-00406 0.02 0.07 0.03 0.05 0.06 0.01 0.04 0.04 −24.16 0.24 −0.024.90 0.20 0.31 0.00 0.00 SEQID-00407 0.02 0.05 0.03 0.07 0.07 0.04 0.070.05 −17.75 0.22 −0.02 5.71 0.21 0.38 0.00 0.21 SEQID-00408 0.02 0.050.06 0.05 0.07 0.02 0.07 0.03 −18.90 0.25 −0.05 4.66 0.22 0.31 0.00 0.00SEQID-00409 0.02 0.03 0.05 0.05 0.07 0.06 0.07 0.06 −18.43 0.31 −0.034.61 0.22 0.33 0.21 0.21 SEQID-00410 0.02 0.05 0.04 0.06 0.10 0.02 0.060.05 −15.30 0.48 −0.04 4.32 0.00 0.31 0.23 0.00 SEQID-00411 0.03 0.040.04 0.06 0.06 0.03 0.06 0.08 −20.87 0.35 −0.02 5.28 0.19 0.33 0.00 0.22SEQID-00412 0.02 0.06 0.06 0.06 0.06 0.03 0.09 0.06 −18.00 0.33 −0.034.78 0.20 0.33 0.18 0.20 SEQID-00413 0.01 0.05 0.04 0.10 0.10 0.04 0.060.06 −15.67 0.31 −0.04 4.36 0.21 0.34 0.00 0.22 SEQID-00414 0.01 0.050.05 0.07 0.07 0.03 0.09 0.06 −16.00 0.35 −0.03 4.79 0.19 0.34 0.20 0.21SEQID-00415 0.02 0.05 0.05 0.07 0.06 0.05 0.08 0.06 −16.54 0.34 −0.034.83 0.19 0.33 0.00 0.21 SEQID-00416 0.01 0.04 0.05 0.04 0.09 0.03 0.070.07 −16.52 0.36 −0.05 4.28 0.21 0.34 0.00 0.20 SEQID-00417 0.02 0.040.04 0.07 0.06 0.04 0.06 0.06 −17.25 0.33 −0.01 6.40 0.21 0.33 0.22 0.00SEQID-00418 0.03 0.04 0.04 0.06 0.07 0.06 0.06 0.06 −16.75 0.27 −0.044.69 0.23 0.33 0.00 0.20 SEQID-00419 0.02 0.04 0.05 0.06 0.06 0.04 0.080.06 −16.77 0.32 −0.04 4.34 0.26 0.36 0.00 0.21 SEQID-00420 0.00 0.040.02 0.09 0.11 0.03 0.04 0.06 −17.45 0.28 0.00 6.65 0.27 0.41 0.23 0.21SEQID-00421 0.01 0.06 0.05 0.07 0.06 0.05 0.08 0.06 −15.20 0.37 −0.034.87 0.20 0.37 0.20 0.20 SEQID-00422 0.02 0.06 0.04 0.10 0.06 0.01 0.090.06 −18.05 0.33 −0.03 4.46 0.23 0.39 0.22 0.21 SEQID-00423 0.01 0.050.03 0.05 0.05 0.06 0.09 0.05 −21.13 0.21 −0.03 5.23 0.23 0.36 0.00 0.21SEQID-00424 0.02 0.04 0.04 0.06 0.08 0.04 0.11 0.05 −16.16 0.36 −0.054.29 1.00 1.00 0.19 0.21 SEQID-00425 0.01 0.07 0.04 0.05 0.04 0.03 0.070.06 −22.68 0.27 −0.03 5.42 0.19 0.32 0.20 0.20 SEQID-00426 0.00 0.080.04 0.05 0.07 0.03 0.06 0.06 −17.18 0.38 −0.03 4.81 0.00 0.31 0.00 0.24SEQID-00427 0.01 0.07 0.07 0.06 0.07 0.02 0.06 0.06 −13.64 0.49 −0.015.68 0.22 0.34 0.21 0.23 SEQID-00428 0.34 0.00 0.00 0.01 0.04 0.00 0.020.00 −36.89 0.05 −0.09 4.42 0.22 0.22 0.00 0.18 SEQID-00429 0.00 0.000.00 0.01 0.04 0.00 0.02 0.00 −43.92 0.00 −0.01 6.93 0.23 0.23 0.25 0.34SEQID-00430 0.34 0.00 0.00 0.01 0.04 0.00 0.02 0.00 −36.89 0.05 −0.094.42 0.27 0.22 0.00 0.18 SEQID-00431 0.00 0.00 0.00 0.01 0.04 0.00 0.020.00 −43.92 0.00 −0.01 6.93 0.28 0.23 0.25 0.34 SEQID-00432 0.00 0.000.00 0.01 0.04 0.00 0.02 0.00 −58.85 0.00 0.23 10.67 0.31 0.25 0.29 0.29SEQID-00433 0.00 0.00 0.00 0.01 0.04 0.00 0.02 0.00 −58.85 0.00 0.2311.81 0.36 0.30 0.23 0.31 SEQID-00434 0.00 0.00 0.00 0.01 0.04 0.00 0.020.00 −39.46 0.00 −0.09 4.42 0.35 0.29 0.22 0.26 SEQID-00435 0.00 0.000.00 0.01 0.02 0.00 0.02 0.00 −40.87 0.16 0.02 9.33 0.38 0.31 0.29 0.00SEQID-00436 0.03 0.07 0.00 0.00 0.08 0.05 0.00 0.05 −38.16 0.28 −0.065.16 0.28 0.22 0.00 0.00 SEQID-00437 0.03 0.07 0.00 0.00 0.11 0.05 0.000.05 −26.97 0.35 0.36 12.12 0.28 0.23 0.00 0.00 SEQID-00438 0.00 0.000.00 0.01 0.04 0.00 0.02 0.00 −36.42 0.27 −0.09 4.42 0.32 0.26 0.27 0.00SEQID-00439 0.00 0.00 0.00 0.01 0.04 0.00 0.02 0.10 −36.42 0.25 −0.094.42 0.33 0.27 0.00 0.00 SEQID-00440 0.00 0.15 0.00 0.01 0.04 0.00 0.020.00 −36.51 0.19 −0.09 4.42 0.33 0.27 0.00 0.29 SEQID-00441 0.00 0.000.00 0.01 0.04 0.18 0.02 0.00 −37.14 0.07 −0.09 4.42 0.30 0.25 0.30 0.00SEQID-00442 0.00 0.00 0.00 0.01 0.15 0.00 0.02 0.00 −37.04 0.07 −0.094.42 0.35 0.23 0.00 0.25 SEQID-00443 0.13 0.00 0.00 0.01 0.04 0.00 0.020.00 −36.60 0.15 −0.09 4.42 0.30 0.25 0.00 0.00 SEQID-00444 0.00 0.000.00 0.01 0.04 0.00 0.02 0.01 −38.92 0.05 −0.06 6.07 0.33 0.27 0.00 0.32SEQID-00445 0.00 0.00 0.00 0.01 0.04 0.00 0.02 0.00 −37.58 0.04 −0.094.42 0.33 0.27 0.00 0.00 SEQID-00446 0.00 0.00 0.00 0.01 0.04 0.00 0.020.00 −38.20 0.17 −0.06 4.55 0.37 0.30 0.00 0.00 SEQID-00447 0.00 0.000.00 0.01 0.04 0.00 0.02 0.00 −45.68 0.04 0.05 9.76 0.35 0.28 0.26 0.31SEQID-00448 0.00 0.00 0.00 0.01 0.04 0.00 0.02 0.00 −45.68 0.04 0.0511.23 0.38 0.31 0.00 0.00 SEQID-00449 0.00 0.00 0.00 0.01 0.04 0.00 0.020.00 −36.42 0.32 −0.09 4.42 0.27 0.22 0.00 0.00 SEQID-00450 0.00 0.000.00 0.01 0.04 0.00 0.02 0.28 −36.42 0.28 −0.09 4.42 0.29 0.23 0.00 0.00SEQID-00451 0.00 0.37 0.00 0.01 0.04 0.00 0.02 0.00 −36.67 0.12 −0.094.42 0.24 0.20 0.23 0.29 SEQID-00452 0.00 0.00 0.00 0.01 0.03 0.42 0.020.00 −38.31 0.00 −0.09 4.42 0.74 0.20 0.26 0.22 SEQID-00453 0.00 0.000.00 0.01 0.33 0.00 0.02 0.00 −38.04 0.00 −0.09 4.42 0.30 0.24 0.20 0.31SEQID-00454 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 −46.29 0.00 0.6713.81 0.37 0.28 0.00 0.27 SEQID-00455 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 −38.19 0.38 0.55 13.66 0.32 0.24 0.30 0.00 SEQID-00456 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 −30.09 0.62 0.43 13.62 0.33 0.25 0.00 0.00SEQID-00457 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 −53.15 0.00 −0.672.38 0.36 0.27 0.31 0.39 SEQID-00458 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 −43.89 0.46 −0.55 2.44 0.32 0.24 0.37 0.34 SEQID-00459 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 −34.54 0.80 −0.43 2.56 0.37 0.27 0.00 0.39SEQID-00460 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 −49.89 0.00 −0.035.00 0.39 0.29 0.00 0.33 SEQID-00461 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 −40.78 0.40 0.05 10.57 0.36 0.27 0.00 0.00 SEQID-00462 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 −32.52 0.72 −0.03 4.79 0.34 0.26 0.00 0.00SEQID-00463 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 −46.29 0.10 0.6713.81 0.33 0.25 0.30 0.00 SEQID-00464 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 −40.50 0.37 0.58 13.76 0.28 0.21 0.00 0.00 SEQID-00465 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 −33.56 0.58 0.48 13.62 0.33 0.25 0.00 0.30SEQID-00466 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 −53.15 0.15 −0.672.38 0.35 0.27 0.34 0.43 SEQID-00467 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 −46.49 0.45 −0.58 2.44 0.34 0.25 0.38 0.34 SEQID-00468 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 −38.56 0.69 −0.48 2.50 0.32 0.24 0.00 0.35SEQID-00469 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 −49.95 0.13 −0.034.97 0.33 0.25 0.00 0.33 SEQID-00470 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 −43.82 0.43 −0.05 4.72 0.31 0.23 0.00 0.00 SEQID-00471 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 −36.05 0.60 0.02 9.27 0.33 0.25 0.00 0.30SEQID-00472 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 −48.60 0.28 0.7013.83 0.29 0.22 0.00 0.31 SEQID-00473 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 −40.50 0.43 0.58 13.56 0.32 0.24 0.00 0.00 SEQID-00474 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 −33.56 0.90 0.48 13.68 0.31 0.23 0.00 0.00SEQID-00475 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 −55.80 0.32 −0.702.36 0.32 0.24 0.37 0.39 SEQID-00476 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 −46.64 0.53 −0.58 2.40 0.28 0.21 0.30 0.32 SEQID-00477 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 −38.51 1.01 −0.48 2.52 0.35 0.26 0.29 0.00SEQID-00478 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 −52.37 0.31 −0.035.03 0.32 0.24 0.00 0.30 SEQID-00479 0.00 0.00 0.00 0.00 0.00 0.00 0.000.00 −42.55 0.44 0.18 11.72 0.35 0.26 0.00 0.30 SEQID-00480 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 −36.35 0.97 −0.05 4.63 0.32 0.24 0.00 0.00SEQID-00481 0.02 0.10 0.06 0.04 0.08 0.05 0.09 0.05 −11.08 0.66 0.0710.46 0.22 0.30 0.00 0.00 SEQID-00482 0.05 0.02 0.02 0.07 0.04 0.01 0.000.04 −27.29 0.18 −0.08 4.37 0.24 0.35 0.00 0.00 SEQID-00483 0.01 0.030.05 0.16 0.10 0.04 0.06 0.07 −12.63 0.44 0.00 7.74 0.18 0.31 0.22 0.23SEQID-00484 0.00 0.07 0.02 0.05 0.03 0.01 0.01 0.02 −33.66 0.11 −0.134.08 0.23 0.32 0.00 0.21 SEQID-00485 0.02 0.11 0.03 0.05 0.05 0.01 0.110.03 −20.39 0.29 0.01 8.37 0.21 0.30 0.00 0.00 SEQID-00486 0.09 0.040.05 0.07 0.07 0.04 0.06 0.05 −14.98 0.69 −0.05 4.44 0.21 0.31 0.00 0.19SEQID-00487 0.06 0.09 0.04 0.06 0.07 0.05 0.06 0.09 −12.20 0.88 0.029.25 0.21 0.29 0.00 0.19 SEQID-00488 0.02 0.08 0.04 0.01 0.06 0.02 0.050.07 −20.86 0.42 0.00 7.03 0.22 0.31 0.19 0.00 SEQID-00489 0.01 0.060.05 0.06 0.06 0.06 0.01 0.06 −24.06 0.27 −0.03 5.17 0.24 0.31 0.00 0.22SEQID-00490 0.06 0.09 0.03 0.07 0.06 0.01 0.02 0.12 −9.86 1.25 −0.034.30 0.20 0.31 0.00 0.22 SEQID-00491 0.05 0.02 0.03 0.05 0.02 0.02 0.030.05 −30.76 0.15 0.22 11.99 0.21 0.31 0.21 0.23 SEQID-00492 0.02 0.020.04 0.04 0.03 0.05 0.09 0.06 −25.46 0.19 0.21 11.95 0.21 0.31 0.00 0.20SEQID-00493 0.06 0.02 0.03 0.04 0.03 0.01 0.01 0.03 −32.41 0.15 0.049.50 0.25 0.34 0.23 0.21 SEQID-00494 0.01 0.07 0.01 0.05 0.03 0.02 0.060.09 −17.65 0.90 0.03 9.78 0.18 0.31 0.19 0.22 SEQID-00495 0.02 0.040.05 0.05 0.03 0.02 0.01 0.06 −29.07 0.23 0.01 8.19 0.24 0.35 0.00 0.24SEQID-00496 0.03 0.03 0.03 0.07 0.02 0.03 0.02 0.07 −30.33 0.30 −0.124.11 0.00 0.31 0.00 0.22 SEQID-00497 0.01 0.11 0.05 0.03 0.02 0.00 0.050.05 −18.49 0.58 −0.03 4.75 0.00 0.31 0.00 0.26 SEQID-00498 0.05 0.040.02 0.05 0.04 0.00 0.02 0.08 −19.54 0.57 0.00 6.55 0.23 0.52 0.00 0.24SEQID-00499 0.01 0.02 0.05 0.03 0.05 0.02 0.04 0.06 −19.08 0.62 −0.016.25 0.27 0.32 0.26 0.25 SEQID-00500 0.02 0.06 0.04 0.02 0.06 0.05 0.060.07 −15.40 0.43 −0.01 6.65 0.26 0.30 0.26 0.26 SEQID-00501 0.04 0.120.05 0.06 0.05 0.06 0.07 0.05 −16.94 0.34 −0.03 4.74 0.21 0.29 0.22 0.24SEQID-00502 0.01 0.09 0.03 0.05 0.04 0.01 0.05 0.06 −20.99 0.33 0.007.18 0.23 0.32 0.25 0.25 SEQID-00503 0.01 0.04 0.03 0.04 0.04 0.01 0.040.04 −29.34 0.19 0.22 11.43 0.23 0.31 0.23 0.24 SEQID-00504 0.03 0.030.03 0.06 0.11 0.04 0.02 0.09 −11.10 0.46 0.02 9.37 0.22 0.30 0.28 0.24SEQID-00505 0.03 0.02 0.04 0.06 0.07 0.01 0.05 0.08 −22.47 0.46 −0.034.82 0.22 0.29 0.00 0.26 SEQID-00506 0.00 0.11 0.03 0.04 0.04 0.07 0.080.07 −11.44 1.03 0.02 9.04 0.20 0.30 0.00 0.22 SEQID-00507 0.05 0.120.06 0.07 0.05 0.04 0.06 0.05 −19.34 0.32 −0.01 5.15 0.25 0.33 0.00 0.24SEQID-00508 0.03 0.06 0.03 0.05 0.06 0.03 0.03 0.13 −17.01 0.60 −0.016.50 0.27 0.32 0.22 0.00 SEQID-00509 0.02 0.03 0.01 0.04 0.02 0.01 0.010.02 −39.60 0.07 0.05 10.23 0.25 0.35 0.22 0.00 SEQID-00510 0.03 0.070.04 0.04 0.04 0.03 0.05 0.04 −25.37 0.32 −0.03 4.91 0.21 0.32 0.24 0.23SEQID-00511 0.03 0.06 0.06 0.04 0.06 0.02 0.10 0.06 −16.64 0.38 −0.016.12 0.22 0.30 0.22 0.00 SEQID-00512 0.02 0.05 0.02 0.05 0.03 0.07 0.040.05 −10.38 0.87 0.03 9.59 0.24 0.35 0.28 0.24 SEQID-00513 0.13 0.000.07 0.05 0.03 0.01 0.12 0.04 −6.89 0.52 0.01 8.00 0.26 0.34 0.00 0.23SEQID-00514 0.01 0.01 0.04 0.04 0.04 0.01 0.01 0.13 −19.37 0.48 0.1011.46 0.00 0.34 0.00 0.23 SEQID-00515 0.01 0.05 0.02 0.05 0.07 0.01 0.060.01 −25.21 0.03 −0.07 4.34 0.27 0.33 0.23 0.22 SEQID-00516 0.02 0.030.06 0.05 0.07 0.02 0.05 0.06 −20.21 0.76 0.00 6.92 0.22 0.32 0.00 0.00SEQID-00517 0.01 0.07 0.02 0.07 0.04 0.01 0.01 0.04 −29.09 0.17 0.2211.90 0.17 0.33 0.21 0.26 SEQID-00518 0.03 0.02 0.04 0.04 0.06 0.01 0.040.13 −22.45 0.33 0.08 10.62 0.24 0.33 0.00 0.25 SEQID-00519 0.05 0.030.04 0.02 0.04 0.03 0.04 0.05 −18.59 0.62 −0.04 4.41 0.27 0.35 0.21 0.25SEQID-00520 0.05 0.02 0.02 0.04 0.02 0.01 0.02 0.04 −32.61 0.15 0.049.81 0.25 0.33 0.26 0.24 SEQID-00521 0.04 0.02 0.02 0.06 0.06 0.00 0.110.06 −16.77 0.44 0.00 6.60 0.23 0.30 0.21 0.25 SEQID-00522 0.04 0.030.01 0.04 0.13 0.00 0.01 0.01 −25.65 0.04 0.02 9.76 0.23 0.32 0.22 0.25SEQID-00523 0.04 0.09 0.06 0.04 0.11 0.03 0.05 0.02 −12.76 0.65 0.006.65 0.27 0.19 0.32 0.26 SEQID-00524 0.03 0.06 0.06 0.11 0.04 0.02 0.040.09 −18.82 0.26 0.05 10.11 0.27 0.23 0.25 0.23 SEQID-00525 0.02 0.050.02 0.02 0.06 0.00 0.02 0.11 −27.49 0.79 −0.01 6.80 0.32 0.30 0.00 1.00SEQID-00526 0.09 0.09 0.03 0.06 0.06 0.00 0.00 0.05 −18.31 0.55 0.078.61 0.31 0.29 0.34 0.30 SEQID-00527 0.04 0.02 0.04 0.06 0.08 0.02 0.060.07 −17.85 0.43 −0.01 5.74 0.29 0.29 0.27 0.28 SEQID-00528 0.01 0.050.04 0.07 0.11 0.00 0.02 0.08 −16.90 0.49 0.03 9.51 0.29 0.29 0.23 0.29SEQID-00529 0.09 0.05 0.03 0.08 0.05 0.00 0.07 0.06 −21.10 0.31 0.006.83 0.00 0.28 0.00 0.00 SEQID-00530 0.04 0.03 0.04 0.05 0.04 0.00 0.030.10 −9.31 0.92 0.08 9.06 0.32 0.32 0.29 0.30 SEQID-00531 0.07 0.06 0.050.05 0.09 0.00 0.03 0.04 −15.35 0.71 0.01 7.73 0.26 0.28 0.25 0.26SEQID-00532 0.04 0.03 0.03 0.08 0.05 0.00 0.06 0.15 −17.89 0.60 −0.015.70 0.21 0.30 0.00 0.00 SEQID-00533 0.02 0.07 0.07 0.01 0.07 0.00 0.030.11 −24.25 0.43 0.06 10.72 0.29 0.32 0.00 0.25 SEQID-00534 0.04 0.050.02 0.06 0.05 0.02 0.06 0.06 −24.70 0.24 −0.02 4.91 0.26 0.30 0.29 0.27SEQID-00535 0.01 0.04 0.03 0.16 0.07 0.02 0.06 0.06 −11.86 0.30 0.018.20 0.22 0.28 0.27 0.28 SEQID-00536 0.01 0.05 0.02 0.00 0.01 0.00 0.030.02 −32.67 0.27 0.00 7.00 0.21 0.31 0.24 0.27 SEQID-00537 0.01 0.020.01 0.04 0.05 0.00 0.00 0.05 −31.23 0.13 −0.02 5.11 0.29 0.33 0.27 0.22SEQID-00538 0.02 0.07 0.02 0.06 0.06 0.00 0.00 0.05 −22.79 0.30 −0.065.19 0.27 0.30 0.00 0.24 SEQID-00539 0.06 0.03 0.02 0.03 0.04 0.00 0.010.09 −19.20 0.71 0.00 7.52 0.27 0.32 0.00 0.23 SEQID-00540 0.04 0.000.02 0.03 0.07 0.00 0.05 0.07 −26.07 0.29 0.14 11.85 0.22 0.29 0.28 0.00SEQID-00541 0.02 0.03 0.02 0.06 0.02 0.01 0.04 0.09 −19.28 0.56 0.1011.02 0.23 0.30 0.24 0.22 SEQID-00542 0.01 0.01 0.03 0.07 0.00 0.00 0.030.07 −20.95 0.42 0.08 10.68 0.25 0.31 0.26 0.00 SEQID-00543 0.02 0.050.01 0.04 0.10 0.05 0.10 0.07 −19.52 0.31 0.00 7.18 0.00 0.30 0.24 0.25SEQID-00544 0.05 0.01 0.03 0.06 0.07 0.00 0.04 0.05 −17.82 0.44 −0.016.35 0.25 0.33 0.29 0.25 SEQID-00545 0.01 0.08 0.04 0.04 0.04 0.00 0.080.06 −26.17 0.22 −0.01 5.86 0.25 0.31 0.19 0.25 SEQID-00546 0.03 0.020.02 0.06 0.04 0.00 0.04 0.05 −27.22 0.22 −0.08 4.33 0.21 0.31 0.22 0.27SEQID-00547 0.07 0.00 0.04 0.04 0.13 0.00 0.02 0.06 −20.21 0.09 0.039.81 0.25 0.34 0.27 0.24 SEQID-00548 0.03 0.03 0.00 0.04 0.07 0.04 0.000.07 −21.35 0.47 −0.05 4.76 0.30 0.15 0.33 0.33 SEQID-00549 0.02 0.020.03 0.09 0.10 0.03 0.10 0.03 −14.48 0.26 0.06 10.19 0.30 0.23 0.00 0.34SEQID-00550 0.02 0.00 0.01 0.09 0.03 0.02 0.04 0.18 −17.01 0.91 −0.044.37 0.33 0.29 0.00 0.27 SEQID-00551 0.03 0.08 0.03 0.05 0.06 0.00 0.000.07 −17.92 0.64 0.12 10.11 0.32 0.32 0.30 0.31 SEQID-00552 0.16 0.020.00 0.06 0.02 0.02 0.02 0.00 −26.95 0.02 0.02 9.05 0.25 0.24 0.25 0.26SEQID-00553 0.01 0.00 0.24 0.06 0.07 0.00 0.00 0.04 −29.60 0.05 0.007.54 0.33 0.35 0.33 0.34 SEQID-00554 0.03 0.02 0.04 0.04 0.01 0.01 0.050.09 −23.36 0.31 0.16 11.12 0.27 0.34 0.24 0.29 SEQID-00555 0.03 0.030.03 0.02 0.05 0.00 0.04 0.10 −23.32 0.33 0.10 11.21 0.20 0.29 0.24 0.00SEQID-00556 0.01 0.03 0.07 0.02 0.01 0.00 0.03 0.07 −23.75 0.29 0.1711.60 0.23 0.30 0.23 0.26 SEQID-00557 0.02 0.03 0.06 0.13 0.07 0.05 0.020.10 −12.39 0.59 0.02 8.90 0.29 0.33 0.24 0.26 SEQID-00558 0.04 0.030.03 0.05 0.05 0.00 0.06 0.03 −21.91 0.09 0.03 7.88 0.25 0.31 0.28 0.26SEQID-00559 0.02 0.02 0.03 0.02 0.08 0.00 0.04 0.05 −25.27 0.34 −0.015.85 0.00 0.33 0.00 0.00 SEQID-00560 0.01 0.00 0.00 0.07 0.00 0.00 0.000.01 −38.09 0.15 0.02 7.57 0.29 0.30 0.27 0.28 SEQID-00561 0.04 0.130.04 0.04 0.04 0.04 0.01 0.04 −8.41 1.32 0.01 8.53 0.19 0.28 0.21 0.00SEQID-00562 0.01 0.05 0.01 0.04 0.01 0.00 0.01 0.07 −31.55 0.39 −0.163.88 0.24 0.30 0.24 0.25 SEQID-00563 0.05 0.05 0.02 0.04 0.04 0.02 0.040.07 −18.88 0.52 0.03 8.84 0.24 0.31 0.00 0.23 SEQID-00564 0.02 0.040.07 0.06 0.04 0.00 0.03 0.05 −24.85 0.23 0.11 10.77 0.28 0.33 0.26 0.23SEQID-00565 0.01 0.07 0.04 0.06 0.04 0.03 0.03 0.06 −18.34 0.73 0.028.87 0.23 0.31 0.23 0.00 SEQID-00566 0.02 0.03 0.05 0.06 0.06 0.00 0.100.04 −15.35 0.46 0.00 6.76 0.24 0.32 0.25 0.81 SEQID-00567 0.01 0.030.04 0.03 0.04 0.04 0.07 0.07 −25.61 0.22 0.21 12.15 0.23 0.31 0.00 0.22SEQID-00568 0.04 0.05 0.02 0.03 0.05 0.02 0.02 0.06 −26.59 0.30 0.1311.42 0.25 0.33 0.20 0.20 SEQID-00569 0.02 0.06 0.02 0.06 0.13 0.04 0.010.05 −16.16 0.52 0.04 10.35 0.23 0.32 0.00 0.24 SEQID-00570 0.03 0.060.05 0.07 0.04 0.00 0.04 0.11 −15.90 0.43 0.03 9.76 0.23 0.30 0.24 0.00SEQID-00571 0.02 0.09 0.02 0.02 0.03 0.02 0.02 0.12 −18.31 0.58 0.007.24 0.28 0.31 0.21 0.25 SEQID-00572 0.03 0.04 0.05 0.08 0.06 0.00 0.020.04 −26.28 0.23 0.13 10.87 0.28 0.32 0.25 0.26 SEQID-00573 0.03 0.040.05 0.06 0.05 0.00 0.03 0.05 −26.70 0.25 0.13 10.82 0.25 0.32 0.19 0.21SEQID-00574 0.04 0.01 0.05 0.06 0.05 0.00 0.07 0.09 −21.11 0.22 0.1511.42 0.23 0.31 0.00 0.00 SEQID-00575 0.01 0.03 0.08 0.02 0.01 0.00 0.040.07 −24.56 0.26 0.17 11.38 0.24 0.28 0.25 0.25 SEQID-00576 0.01 0.070.05 0.06 0.06 0.01 0.05 0.13 −11.59 0.55 0.00 7.24 0.27 0.31 0.23 0.27SEQID-00577 0.02 0.02 0.03 0.12 0.08 0.00 0.06 0.05 −22.27 0.21 0.1110.74 0.24 0.29 0.00 0.25 SEQID-00578 0.02 0.02 0.03 0.05 0.04 0.00 0.030.05 −28.89 0.26 0.24 11.90 0.24 0.31 0.27 0.25 SEQID-00579 0.01 0.010.04 0.05 0.07 0.00 0.07 0.08 −25.22 0.20 0.25 11.95 0.25 0.30 0.26 0.25SEQID-00580 0.06 0.05 0.01 0.04 0.03 0.01 0.06 0.04 −24.98 0.25 0.2111.84 0.00 0.27 0.00 0.22 SEQID-00581 0.04 0.02 0.04 0.05 0.05 0.00 0.040.13 −25.40 0.28 0.12 11.02 0.23 0.29 0.22 0.00 SEQID-00582 0.01 0.080.03 0.04 0.05 0.01 0.06 0.06 −24.01 0.19 0.11 10.65 0.00 0.32 0.25 0.00SEQID-00583 0.05 0.02 0.05 0.03 0.05 0.00 0.01 0.06 −28.61 0.28 0.2412.14 0.26 0.31 0.21 0.20 SEQID-00584 0.09 0.02 0.04 0.06 0.07 0.03 0.070.02 −18.12 0.37 0.01 8.20 0.24 0.28 0.00 0.21 SEQID-00585 0.04 0.010.02 0.04 0.01 0.00 0.03 0.03 −29.34 0.13 0.03 8.91 0.28 0.30 0.27 0.30SEQID-00586 0.08 0.07 0.07 0.09 0.05 0.00 0.03 0.02 −26.12 0.09 0.0710.60 0.24 0.31 0.17 0.00 SEQID-00587 0.02 0.04 0.04 0.04 0.04 0.00 0.010.11 −19.76 0.50 0.02 9.69 0.27 0.31 0.00 0.26 SEQID-00588 0.02 0.040.04 0.08 0.03 0.02 0.07 0.07 −20.29 0.26 0.18 12.08 0.26 0.29 0.25 0.19SEQID-00589 0.04 0.05 0.05 0.03 0.05 0.00 0.03 0.02 −30.06 0.12 0.0610.32 0.22 0.31 0.25 0.25 SEQID-00590 0.01 0.06 0.04 0.04 0.04 0.00 0.000.08 −24.08 0.36 0.05 10.32 0.30 0.31 0.00 0.00 SEQID-00591 0.01 0.030.04 0.03 0.01 0.00 0.05 0.02 −27.30 0.13 0.09 10.47 0.30 0.32 0.00 0.27SEQID-00592 0.06 0.02 0.02 0.06 0.10 0.02 0.02 0.16 −18.59 0.39 −0.015.02 0.30 0.30 0.26 0.24 SEQID-00593 0.01 0.09 0.05 0.04 0.10 0.04 0.050.03 −16.04 0.63 −0.01 5.76 0.26 0.27 0.00 0.23 SEQID-00594 0.06 0.120.03 0.06 0.06 0.00 0.00 0.05 −19.01 0.53 0.08 8.81 0.30 0.29 0.30 0.28SEQID-00595 0.09 0.13 0.03 0.06 0.06 0.00 0.00 0.02 −18.17 0.56 0.078.61 0.29 0.28 0.30 0.28 SEQID-00596 0.02 0.09 0.01 0.04 0.05 0.02 0.020.05 −22.57 0.60 0.00 7.12 0.34 0.32 0.33 0.29 SEQID-00597 0.02 0.120.02 0.03 0.04 0.00 0.00 0.05 −21.54 0.57 0.11 9.35 0.28 0.26 0.32 0.29SEQID-00598 0.05 0.02 0.04 0.04 0.05 0.05 0.00 0.13 −20.52 0.43 0.059.60 0.30 0.26 0.00 0.99 SEQID-00599 0.01 0.04 0.02 0.09 0.08 0.06 0.040.09 −19.09 0.44 −0.02 5.99 0.22 0.31 0.00 0.20 SEQID-00600 0.04 0.030.05 0.04 0.04 0.03 0.08 0.07 −15.69 0.57 0.04 9.53 0.21 0.30 0.00 0.00SEQID-00601 0.01 0.03 0.04 0.03 0.03 0.05 0.08 0.04 −21.74 0.27 −0.016.72 0.20 0.33 0.00 0.20 SEQID-00602 0.03 0.03 0.01 0.10 0.06 0.01 0.070.06 −20.45 0.28 0.09 10.47 0.22 0.31 0.00 0.22 SEQID-00603 0.00 0.020.03 0.07 0.06 0.08 0.03 0.08 −20.14 0.42 −0.03 5.54 0.21 0.32 0.00 0.20SEQID-00604 0.00 0.05 0.03 0.07 0.08 0.02 0.06 0.08 −17.58 0.35 0.029.31 0.21 0.32 0.00 0.21 SEQID-00605 0.01 0.04 0.04 0.05 0.07 0.01 0.030.05 −20.32 0.40 0.00 6.81 0.21 0.31 0.00 0.00 SEQID-00606 0.02 0.040.04 0.03 0.04 0.01 0.03 0.04 −21.52 0.39 −0.03 6.47 0.21 0.34 0.00 0.21SEQID-00607 0.02 0.04 0.05 0.04 0.06 0.03 0.01 0.05 −22.65 0.19 0.029.92 0.21 0.33 0.17 0.00 SEQID-00608 0.01 0.08 0.05 0.07 0.05 0.02 0.060.03 −18.71 0.25 −0.02 5.97 0.22 0.31 0.23 0.24 SEQID-00609 0.00 0.030.04 0.06 0.06 0.01 0.02 0.05 −27.26 0.10 0.04 10.39 0.21 0.33 0.00 0.21SEQID-00610 0.03 0.06 0.04 0.06 0.05 0.00 0.01 0.05 −20.53 0.46 −0.064.45 0.21 0.32 0.21 0.21 SEQID-00611 0.03 0.06 0.06 0.03 0.05 0.04 0.050.08 −10.14 0.90 0.01 8.79 0.22 0.33 0.00 0.25 SEQID-00612 0.02 0.030.07 0.07 0.02 0.01 0.02 0.10 −14.35 0.60 0.01 7.83 0.24 0.34 0.21 0.23SEQID-00613 0.03 0.02 0.02 0.06 0.04 0.01 0.01 0.04 −23.29 0.20 −0.034.72 0.25 0.33 0.00 0.00 SEQID-00614 0.01 0.08 0.03 0.04 0.07 0.04 0.020.05 −13.56 0.91 0.04 9.96 0.21 0.32 0.22 0.19 SEQID-00615 0.05 0.000.00 0.00 0.02 0.00 0.06 0.00 −27.63 0.18 0.00 6.97 0.43 0.28 0.33 0.36SEQID-00616 0.04 0.03 0.03 0.06 0.05 0.00 0.09 0.05 −24.45 0.32 0.2012.14 0.25 0.27 0.00 0.25 SEQID-00617 0.04 0.06 0.04 0.05 0.07 0.00 0.000.08 −20.90 0.46 0.01 8.23 0.27 0.30 0.00 0.23 SEQID-00618 0.01 0.010.07 0.03 0.03 0.00 0.04 0.08 −21.61 0.44 0.15 11.36 0.26 0.30 0.00 0.27SEQID-00619 0.02 0.04 0.05 0.05 0.04 0.00 0.03 0.04 −27.42 0.25 0.1310.79 0.26 0.33 0.25 0.25 SEQID-00620 0.03 0.01 0.01 0.04 0.05 0.02 0.000.15 −22.84 0.58 −0.07 4.39 0.23 0.31 0.00 0.24 SEQID-00621 0.01 0.030.04 0.08 0.01 0.00 0.03 0.07 −18.26 0.35 0.09 11.09 0.25 0.31 0.27 0.22SEQID-00622 0.02 0.05 0.05 0.06 0.05 0.02 0.08 0.11 −18.79 0.43 −0.025.65 0.26 0.33 0.20 0.00 SEQID-00623 0.03 0.04 0.06 0.05 0.05 0.00 0.030.06 −25.75 0.25 0.13 10.85 0.28 0.31 0.22 0.00 SEQID-00624 0.06 0.030.03 0.06 0.04 0.00 0.00 0.06 −25.21 0.43 −0.07 4.34 0.25 0.34 0.23 0.00SEQID-00625 0.03 0.04 0.02 0.03 0.01 0.02 0.03 0.10 −28.78 0.34 0.1411.14 0.26 0.34 0.23 0.23 SEQID-00626 0.03 0.02 0.03 0.05 0.03 0.01 0.060.08 −21.94 0.44 0.03 9.85 0.24 0.30 0.20 0.18 SEQID-00627 0.02 0.020.02 0.02 0.06 0.01 0.02 0.07 −30.26 0.19 0.08 10.61 0.23 0.30 0.00 0.23SEQID-00628 0.02 0.01 0.03 0.04 0.07 0.01 0.02 0.10 −23.95 0.29 0.0510.21 0.25 0.29 0.22 0.00 SEQID-00629 0.02 0.01 0.06 0.05 0.01 0.00 0.050.07 −25.54 0.24 0.20 11.52 0.18 0.30 0.21 0.22 SEQID-00630 0.02 0.020.05 0.14 0.09 0.02 0.09 0.05 −12.56 0.23 0.01 8.03 0.25 0.34 0.29 0.25SEQID-00631 0.02 0.00 0.02 0.03 0.05 0.00 0.05 0.08 −29.33 0.29 0.1110.97 0.24 0.33 0.29 0.24 SEQID-00632 0.01 0.06 0.02 0.06 0.07 0.00 0.050.07 −22.73 0.35 −0.03 4.74 0.26 0.33 0.25 0.27 SEQID-00633 0.02 0.030.02 0.06 0.02 0.00 0.06 0.06 −29.53 0.07 −0.03 5.00 0.29 0.33 0.00 0.26SEQID-00634 0.02 0.00 0.03 0.07 0.03 0.02 0.05 0.05 −24.75 0.38 0.1511.02 0.22 0.26 0.00 0.24 SEQID-00635 0.02 0.05 0.03 0.06 0.04 0.020.083 0.09 −18.64 0.27 0.16 11.63 0.24 0.30 0.00 0.21 SEQID-00636 0.020.01 0.02 0.02 0.06 0.02 0.04 0.08 −24.50 0.28 0.19 12.27 0.20 0.29 0.000.26 SEQID-00637 0.04 0.05 0.03 0.07 0.08 0.02 0.05 0.02 −22.79 0.130.25 12.25 0.25 0.28 0.25 0.25 SEQID-00638 0.01 0.04 0.06 0.04 0.08 0.000.00 0.10 −26.77 0.32 0.04 10.37 0.25 0.29 0.00 0.28 SEQID-00639 0.030.01 0.00 0.05 0.09 0.02 0.06 0.08 −21.28 0.30 0.19 11.06 0.26 0.29 0.280.23 SEQID-00640 0.04 0.01 0.02 0.04 0.05 0.00 0.11 0.12 −28.97 0.260.14 10.65 0.19 0.27 0.00 0.00 SEQID-00641 0.03 0.06 0.02 0.03 0.04 0.000.02 0.03 −29.69 0.09 0.07 10.79 0.27 0.28 0.00 0.31 SEQID-00642 0.030.08 0.04 0.03 0.03 0.08 0.05 0.04 −23.31 0.20 −0.04 5.02 0.26 0.26 0.000.25 SEQID-00643 0.07 0.05 0.04 0.00 0.04 0.00 0.02 0.05 −26.01 0.390.04 8.90 0.25 0.25 0.27 0.00 SEQID-00644 0.02 0.05 0.02 0.04 0.02 0.020.08 0.14 −21.12 0.33 0.03 9.08 0.27 0.26 0.00 0.27 SEQID-00645 0.050.07 0.08 0.06 0.08 0.04 0.06 0.01 −15.18 0.44 0.02 9.00 0.26 0.25 0.000.26 SEQID-00646 0.03 0.07 0.01 0.03 0.04 0.05 0.08 0.05 −18.27 0.710.09 10.32 0.31 0.28 0.00 0.00 SEQID-00647 0.02 0.00 0.04 0.04 0.04 0.000.00 0.01 −27.75 0.24 0.04 10.19 0.34 0.30 0.27 0.30 SEQID-00648 0.050.05 0.05 0.01 0.04 0.02 0.02 0.04 −33.89 0.16 0.01 7.70 0.27 0.23 0.000.00 SEQID-00649 0.01 0.06 0.07 0.05 0.08 0.01 0.04 0.08 −14.83 0.680.01 7.78 0.25 0.33 0.22 0.22 SEQID-00650 0.02 0.05 0.03 0.06 0.10 0.030.03 0.07 −23.09 0.36 −0.02 4.88 0.27 0.17 0.30 0.35 SEQID-00651 0.040.04 0.03 0.03 0.03 0.03 0.04 0.05 −14.04 0.78 −0.01 6.41 0.25 0.34 0.250.24 SEQID-00652 0.06 0.03 0.05 0.12 0.03 0.00 0.05 0.00 −23.90 0.31−0.04 4.69 0.26 0.27 0.31 1.00 SEQID-00653 0.05 0.04 0.07 0.03 0.05 0.000.01 0.10 −20.09 0.49 0.03 9.96 0.25 0.31 0.22 0.24 SEQID-00654 0.020.04 0.03 0.04 0.06 0.01 0.01 0.06 −19.75 0.51 −0.03 5.30 0.19 0.32 0.220.28 SEQID-00655 0.04 0.04 0.01 0.03 0.05 0.00 0.03 0.07 −25.19 0.32−0.03 4.99 0.20 0.35 0.20 0.00 SEQID-00656 0.00 0.01 0.04 0.05 0.07 0.030.03 0.08 −19.20 0.26 0.00 8.72 0.00 0.36 0.00 0.20 SEQID-00657 0.020.05 0.04 0.04 0.06 0.04 0.06 0.05 −22.10 0.20 0.00 7.80 0.20 0.32 0.000.21 SEQID-00658 0.01 0.03 0.01 0.09 0.04 0.01 0.02 0.05 −26.41 0.230.00 6.84 0.22 0.37 0.20 0.22 SEQID-00659 0.03 0.06 0.04 0.05 0.05 0.050.07 0.07 −17.32 0.26 0.01 8.00 0.22 0.30 0.00 0.21 SEQID-00660 0.020.07 0.02 0.06 0.06 0.01 0.03 0.05 −23.14 0.27 −0.01 5.82 0.24 0.33 0.000.22 SEQID-00661 0.02 0.02 0.03 0.09 0.06 0.01 0.07 0.11 −14.17 0.480.01 8.58 1.00 1.00 0.23 0.22 SEQID-00662 0.02 0.03 0.04 0.09 0.05 0.080.10 0.03 −15.75 0.26 0.00 6.53 0.00 0.33 0.00 0.22 SEQID-00663 0.020.05 0.03 0.08 0.06 0.04 0.07 0.06 −17.59 0.23 0.02 9.22 0.37 0.49 0.240.21 SEQID-00664 0.01 0.06 0.01 0.05 0.09 0.02 0.02 0.09 −20.23 0.270.02 9.02 0.00 0.33 0.00 0.23 SEQID-00665 0.01 0.03 0.03 0.07 0.08 0.010.11 0.07 −17.78 0.25 0.00 6.87 0.22 0.32 0.21 0.21 SEQID-00666 0.030.05 0.02 0.04 0.05 0.00 0.05 0.08 −20.08 0.44 −0.05 4.40 0.55 0.71 0.190.23 SEQID-00667 0.02 0.04 0.02 0.04 0.05 0.02 0.07 0.05 −26.85 0.17−0.01 5.26 0.21 0.33 0.00 0.00 SEQID-00668 0.02 0.03 0.00 0.05 0.08 0.010.07 0.06 −30.38 0.14 0.03 9.69 0.23 0.35 0.00 0.20 SEQID-00669 0.040.04 0.05 0.04 0.05 0.02 0.02 0.04 −21.61 0.30 0.00 6.69 0.00 0.35 0.250.00 SEQID-00670 0.04 0.03 0.05 0.04 0.05 0.02 0.02 0.04 −21.61 0.310.00 6.69 0.00 0.35 0.25 0.00 SEQID-00671 0.05 0.03 0.05 0.04 0.05 0.020.02 0.04 −21.67 0.30 −0.01 6.03 0.00 0.35 0.25 0.00 SEQID-00672 0.040.03 0.05 0.04 0.05 0.02 0.02 0.04 −21.97 0.28 −0.01 6.37 0.00 0.35 0.250.00 SEQID-00673 0.04 0.03 0.05 0.04 0.05 0.02 0.03 0.04 −21.69 0.29−0.01 6.03 0.00 0.35 0.25 0.00 SEQID-00674 0.04 0.03 0.05 0.04 0.05 0.020.02 0.04 −21.66 0.30 −0.01 6.03 0.00 0.32 0.25 0.00 SEQID-00675 0.040.03 0.05 0.04 0.05 0.02 0.02 0.04 −21.68 0.30 −0.01 6.03 0.00 0.32 0.250.00 SEQID-00676 0.04 0.03 0.05 0.04 0.05 0.02 0.02 0.04 −21.66 0.29−0.01 6.03 0.00 0.33 0.25 0.00 SEQID-00677 0.04 0.03 0.05 0.04 0.05 0.020.02 0.04 −21.66 0.31 −0.01 6.03 0.00 0.32 0.25 0.23 SEQID-00678 0.040.03 0.05 0.04 0.05 0.02 0.02 0.04 −21.97 0.28 −0.01 6.37 0.00 0.34 0.250.00 SEQID-00679 0.04 0.03 0.05 0.04 0.05 0.02 0.02 0.04 −21.66 0.31−0.01 6.03 0.00 0.32 0.25 0.23 SEQID-00680 0.04 0.03 0.05 0.04 0.05 0.020.02 0.04 −21.70 0.28 −0.01 6.03 0.00 0.32 0.25 0.00 SEQID-00681 0.040.03 0.05 0.04 0.05 0.02 0.02 0.04 −21.68 0.29 −0.01 6.03 0.00 0.32 0.250.00 SEQID-00682 0.04 0.03 0.05 0.04 0.05 0.02 0.02 0.05 −21.66 0.31−0.01 6.03 0.00 0.32 0.25 0.23 SEQID-00683 0.02 0.05 0.03 0.07 0.07 0.040.07 0.05 −17.73 0.22 −0.02 5.71 0.21 0.38 0.00 0.21 SEQID-00684 0.020.05 0.03 0.06 0.07 0.04 0.06 0.05 −17.50 0.25 −0.01 6.00 0.21 0.39 0.000.22 SEQID-00685 0.02 0.05 0.03 0.07 0.07 0.04 0.06 0.05 −17.72 0.22−0.02 5.71 0.21 0.39 0.00 0.21 SEQID-00686 0.02 0.05 0.03 0.07 0.07 0.040.06 0.05 −17.59 0.22 −0.02 5.84 0.22 0.40 0.00 0.22 SEQID-00687 0.020.05 0.03 0.07 0.07 0.04 0.07 0.05 −17.70 0.22 −0.02 5.59 0.21 0.38 0.000.21 SEQID-00688 0.02 0.05 0.03 0.07 0.07 0.04 0.06 0.05 −17.70 0.23−0.02 5.73 0.21 0.40 0.00 0.21 SEQID-00689 0.02 0.05 0.03 0.07 0.07 0.040.06 0.05 −17.72 0.22 −0.02 5.71 0.21 0.40 0.00 0.22 SEQID-00690 0.020.05 0.03 0.06 0.07 0.04 0.06 0.05 −17.68 0.26 −0.01 6.46 0.22 0.40 0.000.20 SEQID-00691 0.02 0.05 0.03 0.06 0.07 0.04 0.06 0.05 −17.79 0.24−0.01 6.57 0.21 0.39 0.00 0.21 SEQID-00692 0.02 0.05 0.03 0.06 0.07 0.040.06 0.05 −17.59 0.25 −0.01 6.35 0.21 0.40 0.00 0.21 SEQID-00693 0.020.05 0.03 0.06 0.07 0.04 0.06 0.05 −17.85 0.23 −0.01 6.35 0.21 0.39 0.210.21 SEQID-00694 0.02 0.05 0.03 0.06 0.07 0.04 0.06 0.05 −17.74 0.24−0.01 6.24 0.21 0.00 0.00 0.21 SEQID-00695 0.02 0.05 0.03 0.07 0.07 0.040.06 0.05 −17.72 0.22 −0.02 5.71 0.21 0.40 0.00 0.22 SEQID-00696 0.020.05 0.03 0.06 0.07 0.04 0.06 0.05 −17.57 0.26 −0.01 6.85 0.21 0.39 0.000.22 SEQID-00697 0.02 0.05 0.03 0.07 0.07 0.04 0.06 0.05 −17.50 0.25−0.01 6.00 0.22 0.39 0.00 0.21 SEQID-00698 0.03 0.05 0.03 0.07 0.07 0.040.06 0.05 −17.44 0.25 −0.01 6.20 0.21 0.39 0.00 0.21 SEQID-00699 0.020.05 0.03 0.07 0.07 0.04 0.06 0.05 −17.62 0.23 −0.02 5.85 0.21 0.40 0.000.21 SEQID-00700 0.02 0.05 0.03 0.06 0.07 0.04 0.06 0.05 −17.48 0.27−0.01 6.46 0.22 0.39 0.00 0.21 SEQID-00701 0.02 0.05 0.03 0.06 0.07 0.040.06 0.05 −17.57 0.26 −0.01 6.35 0.21 0.39 0.00 0.22 SEQID-00702 0.020.05 0.03 0.06 0.07 0.04 0.06 0.05 −17.59 0.25 −0.01 6.35 0.21 0.39 0.000.22 SEQID-00703 0.02 0.05 0.03 0.07 0.07 0.04 0.06 0.05 −17.80 0.23−0.02 5.85 0.21 0.40 0.00 0.21 SEQID-00704 0.02 0.05 0.03 0.06 0.07 0.040.06 0.05 −17.90 0.24 0.00 6.69 0.21 0.39 0.00 0.21 SEQID-00705 0.020.05 0.03 0.06 0.07 0.04 0.06 0.06 −17.58 0.25 −0.01 6.35 0.22 0.40 0.210.21 SEQID-00706 0.02 0.05 0.03 0.07 0.07 0.03 0.07 0.05 −17.53 0.23−0.02 5.44 0.22 0.40 0.00 0.21 SEQID-00707 0.02 0.05 0.03 0.07 0.07 0.030.07 0.05 −17.53 0.23 −0.02 5.44 0.22 0.40 0.00 0.21 SEQID-00708 0.020.05 0.03 0.07 0.07 0.03 0.07 0.05 −17.53 0.23 −0.02 5.44 0.22 0.40 0.000.21 SEQID-00709 0.02 0.05 0.03 0.07 0.07 0.03 0.07 0.05 −17.53 0.23−0.02 5.44 0.22 0.40 0.00 0.21 SEQID-00710 0.02 0.05 0.03 0.07 0.07 0.040.07 0.05 −17.62 0.22 −0.02 5.845 0.21 0.375 0 0.2083 SEQID-00711 0.020.05 0.03 0.07 0.07 0.04 0.07 0.05 −17.66 0.22 −0.02 5.946 0.21 0.375 00.2083 SEQID-00712 0.02 0.05 0.03 0.07 0.07 0.04 0.07 0.05 −17.64 0.22−0.02 5.844 0.21 0.375 0 0.2083 SEQID-00713 0.02 0.05 0.04 0.07 0.070.04 0.07 0.05 −17.62 0.22 −0.02 5.844 0.21 0.375 0 0.2083 SEQID-007140.02 0.05 0.03 0.07 0.07 0.04 0.07 0.05 −17.63 0.22 −0.02 5.844 0.210.375 0 0.2083 SEQID-00715 0.02 0.05 0.03 0.07 0.07 0.04 0.07 0.05−17.74 0.22 −0.01 5.973 0.21 0.375 0 0.2098 SEQID-00716 0.05 0.03 0.050.04 0.04 0.01 0.03 0.04 −22.86 0.27 0.00 6.68 0.00 0.35 0.25 0.22SEQID-00717 0.02 0.02 0.02 0.06 0.05 0.01 0.04 0.03 −26.21 0.21 0.006.81 0.00 0.37 0.17 0.18 SEQID-00718 0.02 0.02 0.02 0.05 0.04 0.01 0.040.03 −26.84 0.21 0.00 6.67 0.00 0.38 0.17 0.19 SEQID-00719 0.02 0.030.02 0.06 0.04 0.01 0.04 0.04 −26.53 0.21 0.00 6.85 0.00 0.38 0.18 0.18SEQID-00720 0.04 0.01 0.05 0.05 0.06 0.01 0.04 0.06 −17.51 0.47 −0.016.05 0.20 0.33 0.00 0.20 SEQID-00721 0.04 0.04 0.01 0.09 0.03 0.01 0.050.05 −18.44 0.28 0.01 8.63 0.68 0.89 0.21 0.21 SEQID-00722 0.02 0.040.02 0.05 0.09 0.00 0.02 0.05 −23.26 0.35 0.00 7.76 0.22 0.32 0.00 0.00SEQID-00723 0.02 0.04 0.03 0.04 0.04 0.00 0.04 0.05 −24.71 0.36 −0.025.10 0.20 0.35 0.35 0.20 SEQID-00724 0.02 0.08 0.03 0.05 0.07 0.03 0.040.06 −17.74 0.39 −0.01 6.43 0.20 0.34 0.00 0.20 SEQID-00725 0.03 0.030.03 0.10 0.06 0.01 0.05 0.04 −18.15 0.28 0.04 9.15 0.20 0.32 0.00 0.21SEQID-00726 0.05 0.05 0.04 0.05 0.06 0.02 0.06 0.05 −19.47 0.43 −0.035.16 0.21 0.31 0.00 0.22 SEQID-00727 0.03 0.03 0.02 0.06 0.05 0.00 0.080.05 −25.41 0.34 0.00 7.39 0.21 0.32 0.00 0.00 SEQID-00728 0.02 0.090.05 0.05 0.05 0.02 0.04 0.06 −20.49 0.42 0.02 8.79 0.27 0.35 0.00 0.23SEQID-00729 0.01 0.02 0.05 0.07 0.06 0.01 0.01 0.07 −25.53 0.22 −0.104.24 0.17 0.34 0.20 0.22 SEQID-00730 0.02 0.05 0.03 0.05 0.06 0.02 0.060.07 −19.93 0.43 0.00 7.52 0.20 0.33 0.00 0.20 SEQID-00731 0.02 0.010.02 0.07 0.05 0.01 0.03 0.05 −23.80 0.25 −0.02 5.21 0.25 0.36 0.20 0.22SEQID-00732 0.03 0.05 0.05 0.07 0.07 0.01 0.05 0.07 −16.46 0.43 −0.034.71 0.18 0.41 0.19 0.21 SEQID-00733 0.04 0.05 0.04 0.05 0.06 0.02 0.030.09 −20.09 0.45 0.04 9.88 0.21 0.33 0.00 0.21 SEQID-00734 0.02 0.020.02 0.09 0.04 0.01 0.04 0.03 −28.10 0.11 −0.05 4.66 0.23 0.38 0.00 0.21SEQID-00735 0.03 0.04 0.03 0.06 0.06 0.01 0.03 0.05 −20.57 0.37 −0.035.11 0.19 0.39 0.17 0.19 SEQID-00736 0.03 0.06 0.05 0.05 0.04 0.00 0.040.08 −18.67 0.55 −0.02 5.26 0.20 0.34 0.19 0.23 SEQID-00737 0.01 0.010.13 0.07 0.10 0.01 0.08 0.06 −10.66 0.25 0.03 7.94 0.25 0.34 0.23 0.25SEQID-00738 0.01 0.04 0.02 0.08 0.04 0.00 0.04 0.06 −22.90 0.30 0.007.02 0.49 0.70 0.00 0.22 SEQID-00739 0.04 0.04 0.04 0.04 0.05 0.01 0.030.08 −20.80 0.45 0.01 7.95 0.21 0.31 0.00 0.21 SEQID-00740 0.04 0.030.05 0.05 0.05 0.00 0.03 0.05 −24.77 0.34 −0.01 5.84 0.22 0.34 0.00 0.22SEQID-00741 0.02 0.05 0.03 0.07 0.03 0.01 0.06 0.04 −22.26 0.32 −0.016.31 0.21 0.33 0.00 0.21 SEQID-00742 0.03 0.04 0.03 0.05 0.04 0.01 0.030.06 −23.79 0.32 0.00 6.55 0.19 0.37 0.37 0.20 SEQID-00743 0.01 0.000.28 0.02 0.03 0.00 0.00 0.07 −17.20 0.07 0.05 8.50 0.40 0.43 0.31 0.27SEQID-00744 0.02 0.05 0.05 0.05 0.06 0.01 0.04 0.06 −21.41 0.40 −0.034.98 0.18 0.33 0.00 0.20 SEQID-00745 0.02 0.08 0.06 0.04 0.04 0.02 0.050.06 −20.48 0.24 0.00 7.10 0.37 0.56 0.00 0.22 SEQID-00746 0.02 0.030.11 0.03 0.05 0.05 0.03 0.05 −19.27 0.23 −0.01 6.42 0.22 0.32 0.23 0.25SEQID-00747 0.03 0.04 0.04 0.05 0.05 0.00 0.05 0.07 −18.93 0.47 −0.015.90 0.21 0.33 0.00 0.22 SEQID-00748 0.03 0.06 0.06 0.05 0.04 0.02 0.040.06 −18.69 0.48 0.04 10.26 0.19 0.40 0.19 0.21 SEQID-00749 0.02 0.040.06 0.05 0.06 0.01 0.05 0.08 −20.08 0.43 −0.01 6.51 0.00 0.33 0.00 0.20SEQID-00750 0.03 0.06 0.04 0.05 0.05 0.01 0.02 0.06 −22.29 0.42 −0.035.11 0.22 0.33 0.00 0.23 SEQID-00751 0.01 0.02 0.16 0.09 0.04 0.01 0.060.05 −15.46 0.16 0.03 8.07 0.22 0.36 0.20 0.24 SEQID-00752 0.03 0.040.05 0.07 0.08 0.00 0.03 0.07 −21.91 0.33 0.01 9.44 0.21 0.34 0.22 0.21SEQID-00753 0.01 0.05 0.02 0.07 0.05 0.01 0.04 0.04 −20.98 0.47 −0.025.20 0.19 0.35 0.00 0.21 SEQID-00754 0.03 0.02 0.07 0.09 0.03 0.01 0.020.05 −30.38 0.15 −0.04 4.71 0.22 0.35 0.20 0.23 SEQID-00755 0.04 0.050.02 0.06 0.05 0.06 0.04 0.05 −21.04 0.43 −0.03 5.03 0.00 0.32 0.00 0.21SEQID-00756 0.01 0.02 0.20 0.04 0.03 0.01 0.02 0.03 −14.62 0.15 0.007.76 0.59 0.30 0.20 0.39 SEQID-00757 0.02 0.03 0.08 0.12 0.06 0.01 0.020.04 −20.93 0.21 0.00 7.12 0.18 0.38 0.19 0.19 SEQID-00758 0.02 0.040.05 0.06 0.06 0.03 0.05 0.08 −19.05 0.40 −0.01 6.39 0.19 0.33 0.00 0.21SEQID-00759 0.02 0.03 0.04 0.07 0.04 0.03 0.06 0.06 −23.41 0.23 −0.035.04 0.00 0.31 0.21 0.25 SEQID-00760 0.04 0.05 0.05 0.04 0.05 0.01 0.040.07 −21.34 0.43 0.00 6.82 0.20 0.33 0.19 0.21 SEQID-00761 0.00 0.020.10 0.27 0.03 0.00 0.04 0.06 −8.13 0.28 0.02 8.77 0.25 0.52 0.22 0.27SEQID-00762 0.02 0.08 0.02 0.02 0.03 0.02 0.02 0.11 −19.85 0.47 0.017.35 0.26 0.30 0.25 0.25 SEQID-00763 0.05 0.05 0.04 0.05 0.06 0.02 0.060.05 −19.53 0.43 −0.03 5.15 0.21 0.31 0.00 0.22 SEQID-00764 0.02 0.070.04 0.07 0.05 0.01 0.03 0.08 −17.08 0.44 0.02 8.94 0.25 0.34 0.26 0.27SEQID-00765 0.02 0.04 0.02 0.04 0.04 0.03 0.03 0.04 −25.78 0.23 −0.044.94 0.16 0.36 0.18 0.19 SEQID-00766 0.05 0.07 0.03 0.05 0.05 0.02 0.050.06 −19.72 0.34 −0.06 4.46 0.40 0.54 0.00 0.22 SEQID-00767 0.03 0.040.05 0.04 0.06 0.01 0.04 0.08 −22.21 0.39 0.03 9.56 0.22 0.35 0.21 0.22SEQID-00768 0.03 0.04 0.04 0.04 0.06 0.01 0.04 0.06 −23.12 0.37 −0.034.87 0.68 0.90 0.00 0.21 SEQID-00769 0.04 0.03 0.02 0.06 0.04 0.01 0.060.04 −26.06 0.29 −0.07 4.36 0.22 0.33 0.23 0.00 SEQID-00770 0.03 0.060.04 0.05 0.05 0.01 0.06 0.08 −19.57 0.40 −0.05 4.68 0.80 0.90 0.22 0.22SEQID-00771 0.03 0.04 0.04 0.05 0.03 0.01 0.04 0.05 −23.12 0.39 −0.015.89 0.21 0.36 0.00 0.22 SEQID-00772 0.02 0.05 0.03 0.04 0.03 0.02 0.080.05 −24.11 0.37 −0.05 4.75 0.20 0.33 0.00 0.20 SEQID-00773 0.02 0.040.01 0.04 0.03 0.03 0.03 0.03 −27.93 0.22 −0.06 4.57 0.17 0.36 0.18 0.18SEQID-00774 0.01 0.04 0.09 0.07 0.05 0.04 0.01 0.06 −19.68 0.37 0.0810.85 0.23 0.32 0.00 0.25 SEQID-00775 0.01 0.02 0.04 0.07 0.05 0.01 0.020.06 −21.83 0.29 0.04 9.61 0.19 0.37 0.22 0.21 SEQID-00776 0.02 0.080.01 0.10 0.04 0.00 0.03 0.05 −16.79 0.24 −0.01 5.68 0.82 0.91 0.21 0.22SEQID-00777 0.03 0.03 0.02 0.03 0.03 0.01 0.03 0.04 −28.02 0.23 −0.025.49 0.18 0.42 0.17 0.18 SEQID-00778 0.02 0.04 0.01 0.03 0.03 0.01 0.020.03 −29.55 0.22 −0.02 5.34 0.19 0.42 0.18 0.18 SEQID-00779 0.03 0.050.04 0.05 0.05 0.02 0.04 0.07 −18.79 0.42 −0.01 6.24 0.19 0.34 0.19 0.19SEQID-00780 0.03 0.05 0.04 0.06 0.06 0.01 0.08 0.06 −22.58 0.29 0.028.69 1.00 1.00 0.18 0.00 SEQID-00781 0.04 0.04 0.01 0.09 0.03 0.01 0.050.05 −18.68 0.26 0.01 8.78 0.89 0.89 0.21 0.21 SEQID-00782 0.02 0.030.02 0.07 0.05 0.00 0.04 0.05 −26.50 0.17 −0.04 4.77 0.30 0.44 0.00 0.21SEQID-00783 0.03 0.04 0.02 0.06 0.07 0.03 0.04 0.06 −22.76 0.29 −0.016.25 0.00 0.31 0.00 0.22 SEQID-00784 0.02 0.03 0.03 0.04 0.05 0.00 0.030.06 −25.48 0.36 0.01 8.05 0.20 0.34 0.43 0.22 SEQID-00785 0.03 0.040.05 0.04 0.06 0.02 0.04 0.09 −20.73 0.43 0.03 9.50 0.23 0.32 0.00 0.22SEQID-00786 0.03 0.05 0.03 0.05 0.05 0.01 0.05 0.05 −28.05 0.31 −0.054.66 0.65 0.88 0.00 0.21 SEQID-00787 0.04 0.10 0.02 0.07 0.03 0.02 0.070.05 −16.15 0.45 0.05 10.26 0.22 0.33 0.00 0.19 SEQID-00788 0.03 0.040.05 0.04 0.06 0.00 0.04 0.08 −17.76 0.53 −0.03 4.92 0.22 0.36 0.23 0.22SEQID-00789 0.02 0.03 0.03 0.04 0.03 0.05 0.02 0.05 −23.69 0.42 0.039.29 0.24 0.35 0.00 0.00 SEQID-00790 0.02 0.02 0.04 0.02 0.05 0.00 0.030.04 −25.14 0.25 0.11 10.51 0.22 0.30 0.27 0.00 SEQID-00791 0.02 0.060.06 0.04 0.04 0.02 0.04 0.05 −18.94 0.44 0.01 7.91 0.18 0.34 0.21 0.22SEQID-00792 0.03 0.05 0.02 0.05 0.05 0.01 0.05 0.05 −23.78 0.31 0.007.09 0.18 0.34 0.18 0.18 SEQID-00793 0.03 0.07 0.05 0.05 0.06 0.02 0.070.08 −21.12 0.40 −0.03 5.00 0.25 0.39 0.00 0.00 SEQID-00794 0.02 0.040.04 0.09 0.04 0.01 0.04 0.04 −22.19 0.35 −0.01 6.31 0.20 0.34 0.20 0.20SEQID-00795 0.04 0.03 0.04 0.06 0.05 0.02 0.03 0.07 −18.67 0.51 0.006.89 0.17 0.34 0.18 0.19 SEQID-00796 0.02 0.06 0.04 0.05 0.05 0.01 0.060.07 −19.06 0.46 −0.01 6.44 0.19 0.37 0.19 0.20 SEQID-00797 0.01 0.030.02 0.07 0.04 0.01 0.02 0.04 −24.56 0.24 0.00 6.34 0.22 0.34 0.00 0.22SEQID-00798 0.03 0.07 0.04 0.06 0.05 0.02 0.06 0.07 −19.87 0.41 −0.054.37 0.20 0.33 0.00 0.21 SEQID-00799 0.03 0.06 0.04 0.05 0.04 0.01 0.060.06 −20.28 0.40 0.00 6.88 0.21 0.33 0.20 0.21 SEQID-00800 0.02 0.050.04 0.05 0.06 0.02 0.07 0.05 −23.63 0.24 0.01 8.40 0.90 0.95 0.00 0.00SEQID-00801 0.03 0.03 0.05 0.08 0.05 0.02 0.04 0.05 −26.41 0.21 0.0510.06 0.20 0.33 0.00 0.21 SEQID-00802 0.03 0.04 0.02 0.09 0.03 0.00 0.040.05 −22.03 0.28 0.00 6.55 0.56 0.76 0.00 0.22 SEQID-00803 0.03 0.040.07 0.07 0.02 0.02 0.07 0.04 −19.42 0.33 −0.02 5.12 0.88 0.89 0.00 0.21SEQID-00804 0.03 0.05 0.03 0.06 0.05 0.01 0.05 0.06 −22.56 0.39 0.006.80 0.22 0.33 0.00 0.21 SEQID-00805 0.04 0.05 0.13 0.05 0.04 0.01 0.020.09 −15.61 0.52 −0.03 5.06 0.92 0.94 0.23 0.22 SEQID-00806 0.05 0.050.05 0.06 0.05 0.02 0.06 0.06 −19.07 0.45 −0.02 6.01 0.20 0.30 0.00 0.21SEQID-00807 0.02 0.04 0.04 0.07 0.06 0.02 0.04 0.06 −22.08 0.41 0.017.91 0.20 0.34 0.00 0.20 SEQID-00808 0.03 0.04 0.04 0.06 0.05 0.01 0.040.05 −24.86 0.25 −0.07 4.43 0.19 0.35 0.00 0.20 SEQID-00809 0.02 0.050.09 0.05 0.07 0.01 0.07 0.06 −15.74 0.43 −0.01 6.10 0.84 0.95 0.00 0.24SEQID-00810 0.03 0.06 0.03 0.06 0.04 0.01 0.03 0.07 −21.00 0.44 −0.044.78 0.19 0.32 0.00 0.22 SEQID-00811 0.03 0.06 0.02 0.05 0.06 0.02 0.050.04 −21.49 0.37 −0.02 5.48 0.22 0.32 0.00 0.22 SEQID-00812 0.02 0.050.01 0.09 0.08 0.01 0.05 0.04 −23.69 0.30 −0.07 4.28 0.22 0.31 0.22 0.00SEQID-00813 0.04 0.07 0.04 0.04 0.04 0.03 0.05 0.05 −20.90 0.36 0.006.68 0.20 0.33 0.00 0.21 SEQID-00814 0.02 0.04 0.02 0.06 0.04 0.07 0.030.04 −15.97 0.54 0.06 9.25 1.00 1.00 0.00 0.25 SEQID-00815 0.02 0.070.03 0.06 0.04 0.03 0.06 0.04 −21.94 0.26 −0.02 5.45 0.20 0.33 0.00 0.20SEQID-00816 0.02 0.04 0.03 0.06 0.05 0.01 0.03 0.07 −21.25 0.54 −0.025.30 0.19 0.34 0.00 0.20 SEQID-00817 0.03 0.06 0.03 0.08 0.05 0.02 0.030.05 −17.92 0.47 −0.03 4.98 0.22 0.31 0.00 0.22 SEQID-00818 0.03 0.050.03 0.08 0.04 0.01 0.02 0.04 −22.52 0.26 0.01 8.12 0.19 0.33 0.00 0.20SEQID-00819 0.02 0.03 0.01 0.02 0.06 0.00 0.06 0.08 −23.82 0.30 0.1811.91 0.19 0.28 0.00 0.28 SEQID-00820 0.05 0.05 0.05 0.07 0.05 0.01 0.050.02 −22.32 0.13 0.00 6.55 0.19 0.33 0.19 0.20 SEQID-00821 0.02 0.060.03 0.05 0.05 0.01 0.04 0.05 −27.82 0.30 −0.05 4.54 0.75 0.89 0.00 0.21SEQID-00822 0.03 0.03 0.04 0.04 0.05 0.01 0.01 0.09 −21.46 0.48 0.006.76 0.21 0.33 0.18 0.21 SEQID-00823 0.03 0.05 0.05 0.06 0.04 0.02 0.040.07 −19.60 0.45 0.03 9.21 0.21 0.38 0.00 0.23 SEQID-00824 0.02 0.070.05 0.06 0.05 0.03 0.07 0.06 −18.82 0.38 0.01 7.62 0.43 0.70 0.21 0.21SEQID-00825 0.02 0.04 0.01 0.06 0.05 0.01 0.03 0.03 −27.73 0.20 −0.015.87 0.20 0.34 0.21 0.18 SEQID-00826 0.02 0.05 0.04 0.07 0.05 0.03 0.040.06 −23.22 0.17 −0.06 4.46 0.22 0.32 0.00 0.22 SEQID-00827 0.02 0.050.05 0.09 0.05 0.02 0.04 0.05 −18.66 0.36 −0.01 6.55 0.18 0.33 0.19 0.19SEQID-00828 0.02 0.05 0.04 0.06 0.05 0.00 0.05 0.06 −21.15 0.40 −0.015.88 0.19 0.33 0.00 0.22 SEQID-00829 0.04 0.02 0.03 0.06 0.03 0.01 0.020.04 −27.07 0.18 0.00 6.97 0.19 0.36 0.19 0.17 SEQID-00830 0.05 0.050.04 0.04 0.03 0.02 0.05 0.02 −31.03 0.20 0.03 9.50 0.21 0.31 0.18 0.23SEQID-00831 0.02 0.06 0.03 0.07 0.05 0.03 0.04 0.06 −20.27 0.49 −0.016.52 0.19 0.32 0.00 0.20 SEQID-00832 0.03 0.07 0.07 0.04 0.03 0.03 0.030.05 −19.84 0.49 −0.01 6.35 0.23 0.33 0.24 0.23 SEQID-00833 0.03 0.030.04 0.08 0.05 0.03 0.03 0.06 −18.70 0.04 −0.02 5.99 0.00 0.36 0.00 0.18SEQID-00834 0.03 0.04 0.07 0.06 0.05 0.03 0.04 0.05 −19.80 0.30 0.039.51 0.21 0.33 0.00 0.20 SEQID-00835 0.02 0.06 0.03 0.04 0.05 0.00 0.040.06 −212.75 0.42 0.04 9.78 0.20 0.33 0.00 0.20 SEQID-00836 0.02 0.020.01 0.07 0.05 0.01 0.01 0.04 −28.27 0.15 −0.06 4.67 0.00 0.36 0.16 0.19SEQID-00837 0.01 0.07 0.03 0.04 0.02 0.01 0.04 0.04 −23.16 0.37 0.018.05 0.44 0.59 0.00 0.21 SEQID-00838 0.02 0.09 0.04 0.07 0.07 0.05 0.080.05 −17.20 0.33 −0.04 4.36 0.23 0.43 0.00 0.21 SEQID-00839 0.02 0.090.04 0.07 0.07 0.05 0.08 0.05 −17.20 0.33 −0.04 4.36 0.23 0.43 0.00 0.21SEQID-00840 0.02 0.05 0.06 0.08 0.06 0.03 0.04 0.07 −16.79 0.41 −0.034.92 0.23 0.41 0.00 0.22 SEQID-00841 0.02 0.07 0.06 0.05 0.06 0.03 0.060.08 −15.70 0.45 0.01 8.78 0.21 0.33 0.00 0.21 SEQID-00842 0.02 0.080.05 0.06 0.06 0.07 0.05 0.05 −15.37 0.40 −0.01 6.24 0.21 0.33 0.00 0.20SEQID-00843 0.02 0.05 0.03 0.05 0.04 0.05 0.09 0.04 −19.75 0.35 −0.064.34 0.21 0.33 0.00 0.21 SEQID-00844 0.02 0.08 0.05 0.07 0.04 0.04 0.030.06 −17.13 0.43 0.03 9.49 0.20 0.33 0.00 0.21 SEQID-00845 0.02 0.060.05 0.05 0.06 0.04 0.03 0.05 −19.30 0.37 0.02 8.68 0.20 0.33 0.00 0.21SEQID-00846 0.01 0.07 0.06 0.06 0.03 0.03 0.03 0.08 −19.54 0.47 −0.015.25 0.21 0.37 0.21 0.22 SEQID-00847 0.02 0.07 0.04 0.05 0.06 0.04 0.050.04 −15.64 0.382 0.00 7.17 0.21 0.31 0.35 0.21 SEQID-00848 0.02 0.050.02 0.06 0.06 0.04 0.08 0.04 −20.06 0.27 −0.02 5.45 0.21 0.31 0.29 0.21SEQID-00849 0.02 0.08 0.02 0.09 0.08 0.05 0.08 0.07 −17.01 0.41 −0.064.10 0.25 0.35 0.00 0.22 SEQID-00850 0.01 0.03 0.03 0.12 0.08 0.03 0.080.09 −14.72 0.43 −0.03 4.43 0.22 0.41 0.00 0.23 SEQID-00851 0.01 0.070.06 0.05 0.03 0.04 0.07 0.05 −16.72 0.46 −0.01 5.64 0.25 0.31 0.00 0.00SEQID-00852 0.03 0.08 0.03 0.08 0.06 0.05 0.08 0.06 −11.63 0.39 0.038.62 0.29 0.37 0.00 0.19 SEQID-00853 0.01 0.05 0.06 0.07 0.01 0.03 0.070.05 −21.01 0.41 0.02 8.22 0.28 0.30 0.25 0.26 SEQID-00854 0.02 0.040.05 0.05 0.04 0.03 0.09 0.03 −22.92 0.44 0.01 7.66 0.20 0.28 0.21 0.22SEQID-00855 0.02 0.06 0.03 0.05 0.05 0.02 0.06 0.04 −22.85 0.50 −0.025.69 0.28 0.32 0.23 0.22 SEQID-00856 0.03 0.04 0.05 0.07 0.07 0.02 0.020.05 −21.90 0.38 0.04 9.19 0.21 0.29 0.00 0.00 SEQID-00857 0.02 0.050.06 0.06 0.04 0.04 0.08 0.05 −20.43 0.34 −0.04 4.89 0.21 0.33 0.20 0.21SEQID-00858 0.02 0.05 0.04 0.05 0.07 0.00 0.05 0.04 −19.78 0.44 0.006.90 0.20 0.30 0.00 0.00 SEQID-00859 0.02 0.03 0.04 0.09 0.07 0.00 0.010.03 −22.27 0.41 −0.01 6.68 0.20 0.33 0.23 0.22 SEQID-00860 0.03 0.030.02 0.06 0.05 0.00 0.08 0.05 −25.41 0.34 0.00 7.39 0.21 0.32 0.00 0.00SEQID-00861 0.05 0.05 0.04 0.05 0.06 0.02 0.06 0.05 −19.53 0.43 −0.035.15 0.21 0.31 0.00 0.22 SEQID-00862 0.05 0.05 0.04 0.05 0.06 0.02 0.060.05 −19.52 0.43 −0.03 5.16 0.21 0.31 0.00 0.22 SEQID-00863 0.02 0.040.02 0.03 0.08 0.00 0.02 0.05 −23.67 0.33 0.00 7.90 0.22 0.31 0.23 0.21SEQID-00864 0.07 0.08 0.01 0.03 0.05 0.00 0.01 0.04 −28.98 0.24 −0.153.89 0.44 0.48 0.24 0.19 SEQID-00865 0.08 0.07 0.01 0.03 0.06 0.00 0.010.05 −27.55 0.34 −0.18 3.79 0.39 0.46 0.22 0.24 SEQID-00866 0.06 0.080.01 0.03 0.04 0.00 0.00 0.07 −29.02 0.33 −0.18 3.88 0.39 0.44 0.23 0.24SEQID-00867 0.05 0.07 0.01 0.04 0.05 0.00 0.02 0.04 −28.60 0.33 −0.183.76 0.44 0.49 0.24 0.23 SEQID-00868 0.09 0.10 0.01 0.05 0.04 0.00 0.030.03 −24.77 0.34 −0.12 3.96 0.34 0.45 0.00 0.00 SEQID-00869 0.06 0.070.02 0.01 0.06 0.00 0.01 0.06 −28.16 0.29 −0.14 3.97 0.44 0.47 0.23 0.25SEQID-00870 0.07 0.07 0.01 0.04 0.04 0.02 0.02 0.0a −28.99 0.30 −0.134.03 0.35 0.45 0.00 0.00 SEQID-00871 0.02 0.04 0.04 0.03 0.06 0.00 0.030.06 −25.67 0.29 −0.03 4.94 0.23 0.34 0.00 0.00 SEQID-00872 0.04 0.030.03 0.04 0.07 0.00 0.05 0.08 −25.39 0.32 0.01 8.62 0.00 0.33 0.00 0.2JSEQID-00873 0.03 0.03 0.03 0.04 0.06 0.00 0.06 0.07 −25.16 0.32 0.028.95 0.22 0.33 0.00 0.22 SEQID-00874 0.01 0.04 0.03 0.03 0.03 0.03 0.070.05 −25.15 0.33 −0.08 4.45 0.25 0.31 0.21 0.25 SEQID-00875 0.02 0.040.03 0.03 0.04 0.03 0.07 0.05 −25.71 0.29 −0.08 4.36 0.21 0.34 0.21 0.25SEQID-00876 0.02 0.03 0.02 0.04 0.05 0.05 0.02 0.05 −26.34 0.38 −0.104.27 0.23 0.31 0.22 0.22 SEQID-00877 0.03 0.03 0.02 0.05 0.02 0.02 0.060.07 −27.67 0.29 −0.10 4.27 0.23 0.31 0.00 0.22 SEQID-00878 0.03 0.050.03 0.04 0.03 0.01 0.04 0.06 −26.25 0.35 −0.01 5.48 0.21 0.33 0.00 0.23SEQID-00879 0.03 0.05 0.03 0.05 0.03 0.01 0.04 0.07 −25.44 0.39 0.007.29 0.20 0.31 0.00 0.22 SEQID-00880 0.03 0.02 0.09 0.06 0.01 0.00 0.000.00 −21.21 0.14 0.01 8.06 0.35 0.34 0.34 0.36 SEQID-00881 0.02 0.000.06 0.09 0.13 0.00 0.00 0.01 −15.62 0.24 0.01 7.37 0.27 0.31 0.30 0.31SEQID-00882 0.04 0.01 0.01 0.08 0.05 0.00 0.02 0.02 −29.20 0.07 −0.025.28 0.29 0.30 0.00 0.30 SEQID-00883 0.01 0.05 0.04 0.03 0.04 0.01 0.010.03 −23.50 0.25 0.05 8.55 0.23 0.35 0.25 0.25 SEQID-00884 0.02 0.030.04 0.12 0.02 0.00 0.01 0.04 −19.99 0.33 0.07 10.84 0.23 0.35 0.24 0.23SEQID-00885 0.03 0.04 0.03 0.05 0.04 0.01 0.02 0.03 −20.99 0.15 0.0811.70 0.24 0.37 0.25 0.25 SEQID-00886 0.04 0.06 0.01 0.00 0.04 0.01 0.020.05 −30.02 0.32 0.07 10.21 0.21 0.28 0.21 1.00 SEQID-00887 0.01 0.060.03 0.00 0.03 0.02 0.02 0.07 −32.84 0.06 0.07 10.25 0.29 0.28 0.28 0.27SEQID-00888 0.01 0.03 0.01 0.00 0.03 0.02 0.05 0.04 −44.55 0.23 −0.343.56 0.30 0.29 0.19 0.30 SEQID-00889 0.07 0.04 0.02 0.00 0.01 0.02 0.040.02 −33.51 0.19 −0.10 4.35 0.28 0.32 0.00 0.26 SEQID-00890 0.04 0.020.01 0.00 0.02 0.01 0.04 0.04 −35.96 0.10 −0.02 5.48 0.27 0.35 0.20 0.25SEQID-00891 0.07 0.02 0.00 0.00 0.01 0.01 0.01 0.03 −33.58 0.07 −0.045.39 0.28 0.33 0.25 0.25 SEQID-00892 0.04 0.05 0.03 0.00 0.05 0.02 0.030.03 −29.13 0.16 0.07 10.36 0.29 0.28 0.00 0.26 SEQID-00893 0.01 0.080.03 0.00 0.01 0.04 0.04 0.02 −34.20 0.12 0.07 9.83 0.30 0.26 0.28 0.28SEQID-00894 0.03 0.04 0.01 0.04 0.04 0.01 0.03 0.04 −28.24 0.23 −0.025.45 0.18 0.56 0.18 0.18 SEQID-00895 0.03 0.04 0.01 0.03 0.05 0.01 0.030.04 −28.12 0.24 −0.02 5.53 0.18 0.56 0.18 0.17 SEQID-00896 0.02 0.050.04 0.06 0.07 0.02 0.04 0.08 −21.96 0.34 −0.02 5.52 0.00 0.34 0.00 0.00SEQID-00897 0.03 0.04 0.01 0.04 0.04 0.01 0.03 0.04 −28.40 0.22 −0.025.45 0.19 0.53 0.18 0.18 SEQID-00898 0.05 0.04 0.04 0.05 0.06 0.02 0.060.05 −19.69 0.41 −0.03 5.05 0.19 0.30 0.00 0.20 SEQID-00899 0.05 0.050.04 0.05 0.06 0.02 0.06 0.05 −19.52 0.43 −0.03 5.16 0.21 0.31 0.00 0.22SEQID-00900 0.03 0.04 0.01 0.04 0.04 0.01 0.03 0.04 −27.76 0.23 −0.025.43 0.19 0.54 0.18 0.18 SEQID-00901 0.03 0.06 0.04 0.04 0.04 0.02 0.030.06 −23.59 0.31 0.00 7.14 0.42 0.64 0.00 0.19 SEQID-00902 0.03 0.060.03 0.03 0.04 0.02 0.06 0.06 −22.21 0.34 0.00 7.11 0.19 0.33 0.00 0.20SEQID-00903 0.03 0.04 0.03 0.03 0.04 0.03 0.04 0.03 −24.33 0.29 −0.035.13 0.20 0.36 0.00 0.20 SEQID-00904 0.03 0.04 0.03 0.03 0.04 0.03 0.030.04 −23.52 0.31 −0.03 5.12 0.21 0.35 0.00 0.20 SEQID-00905 0.02 0.000.00 0.04 0.02 0.00 0.03 0.03 −36.76 0.12 −0.09 4.39 0.58 0.69 0.22 0.22SEQID-00906 0.03 0.05 0.04 0.04 0.03 0.01 0.04 0.07 −20.67 0.42 0.017.85 0.85 0.99 0.20 0.22 SEQID-00907 0.02 0.04 0.06 0.04 0.06 0.03 0.050.07 −23.89 0.29 −0.01 5.48 0.19 0.35 0.19 0.20 SEQID-00908 0.03 0.000.00 0.03 0.02 0.00 0.093 0.03 −37.05 0.12 −0.10 4.35 0.56 0.68 0.210.19 SEQID-00909 0.04 0.06 0.03 0.04 0.06 0.02 0.04 0.09 −17.81 0.470.02 8.58 0.89 0.85 0.00 0.22 SEQID-00910 0.03 0.03 0.03 0.05 0.03 0.030.03 0.09 −18.50 0.56 0.01 8.14 0.23 0.32 0.00 0.21 SEQID-00911 0.020.05 0.04 0.06 0.05 0.03 0.05 0.08 −22.55 0.33 −0.01 6.39 0.18 0.34 0.190.20 SEQID-00912 0.04 0.06 0.06 0.03 0.03 0.00 0.02 0.05 −22.92 0.34−0.04 4.67 0.32 0.46 0.00 0.24 SEQID-00913 0.01 0.06 0.04 0.04 0.05 0.010.05 0.05 −25.08 0.34 −0.02 6.09 1.00 1.00 0.20 0.21 SEQID-00914 0.040.05 0.04 0.04 0.06 0.02 0.09 0.08 −19.09 0.62 −0.02 4.93 0.18 0.35 0.190.20 SEQID-00915 0.04 0.04 0.04 0.04 0.05 0.01 0.09 0.08 −20.80 0.450.01 7.95 0.21 0.31 0.00 0.21 SEQID-00916 0.02 0.07 0.04 0.05 0.05 0.010.05 0.06 −18.96 0.48 0.00 6.80 0.21 0.31 0.00 0.22 SEQID-00917 0.010.07 0.03 0.04 0.05 0.02 0.07 0.06 −21.16 0.25 0.07 8.51 0.21 0.31 0.230.23 SEQID-00918 0.01 0.05 0.07 0.06 0.04 0.05 0.06 0.04 −20.38 0.300.01 7.96 0.22 0.31 0.00 0.22 SEQID-00919 0.04 0.05 0.03 0.05 0.06 0.020.03 0.07 −19.53 0.46 0.01 8.37 0.20 0.34 0.00 0.20 SEQID-00920 0.030.02 0.03 0.05 0.05 0.02 0.09 0.05 −25.14 0.21 0.04 9.57 0.00 0.34 0.000.00 SEQID-00921 0.03 0.07 0.04 0.05 0.06 0.04 0.03 0.05 −18.81 0.420.01 7.80 0.20 0.35 0.00 0.21 SEQID-00922 0.04 0.01 0.03 0.04 0.03 0.020.02 0.05 −31.38 0.24 0.08 10.51 0.25 0.34 0.00 0.20 SEQID-00923 0.020.05 0.06 0.04 0.06 0.02 0.04 0.09 −23.98 0.32 0.00 6.83 0.19 0.36 0.190.20 SEQID-00924 0.02 0.05 0.07 0.05 0.07 0.01 0.04 0.09 −18.81 0.32−0.02 5.87 0.00 0.39 0.16 0.22 SEQID-00925 0.04 0.01 0.00 0.02 0.03 0.010.02 0.04 −33.82 0.22 −0.05 4.71 0.49 0.68 0.23 0.00 SEQID-00926 0.040.05 0.04 0.05 0.04 0.02 0.02 0.09 −20.25 0.45 0.01 8.46 0.23 0.33 0.210.23 SEQID-00927 0.05 0.09 0.03 0.03 0.05 0.01 0.02 0.05 −25.17 0.31−0.04 4.62 0.39 0.58 0.23 0.00 SEQID-00928 0.06 0.02 0.03 0.04 0.03 0.010.01 0.03 −32.56 0.15 0.04 9.50 0.25 0.34 0.23 0.21 SEQID-00929 0.010.04 0.04 0.04 0.05 0.03 0.02 0.09 −19.07 0.45 0.00 6.93 0.84 0.83 0.200.23 SEQID-00930 0.01 0.10 0.08 0.07 0.04 0.02 0.02 0.05 −23.31 0.290.01 7.38 0.25 0.35 0.23 0.23 SEQID-00931 0.02 0.01 0.04 0.02 0.02 0.010.09 0.03 −38.39 0.06 −0.01 6.23 0.23 0.36 0.23 0.25 SEQID-00932 0.020.05 0.05 0.04 0.05 0.02 0.04 0.06 −22.04 0.35 0.01 8.31 0.38 0.56 0.210.21 SEQID-00933 0.02 0.04 0.02 0.06 0.05 0.00 0.04 0.05 −25.40 0.19−0.03 4.94 0.30 0.45 0.20 0.22 SEQID-00934 0.04 0.06 0.04 0.05 0.06 0.030.09 0.08 −18.24 0.65 −0.02 4.99 0.19 0.35 0.19 0.19 SEQID-00935 0.030.04 0.05 0.04 0.06 0.00 0.04 0.08 −17.76 0.53 −0.03 4.92 0.22 0.36 0.230.22 SEQID-00936 0.04 0.03 0.04 0.03 0.05 0.05 0.03 0.04 −23.52 0.270.03 9.32 0.22 0.28 0.21 0.00 SEQID-00937 0.02 0.05 0.05 0.05 0.04 0.030.06 0.06 −19.26 0.38 0.00 6.76 0.18 0.35 0.18 0.19 SEQID-00938 0.030.06 0.04 0.04 0.06 0.03 0.05 0.06 −20.58 0.35 0.02 8.95 0.21 0.31 0.000.21 SEQID-00939 0.02 0.04 0.03 0.06 0.04 0.00 0.04 0.07 −19.40 0.450.02 9.64 0.21 0.33 0.00 0.22 SEQID-00940 0.01 0.06 0.06 0.06 0.05 0.000.03 0.08 −18.74 0.44 0.00 6.43 0.00 0.55 0.17 0.86 SEQID-00941 0.050.07 0.08 0.02 0.05 0.00 0.02 0.04 −24.70 0.26 −0.04 4.72 0.30 0.48 0.190.23 SEQID-00942 0.03 0.05 0.09 0.04 0.02 0.00 0.09 0.08 −23.23 0.35−0.02 5.20 0.28 0.42 0.00 0.24 SEQID-00943 0.02 0.05 0.04 0.07 0.05 0.030.06 0.07 −21.97 0.31 −0.01 6.50 0.18 0.34 0.19 0.19 SEQID-00944 0.050.11 0.04 0.01 0.05 0.00 0.09 0.04 −25.95 0.30 −0.05 4.56 0.40 0.58 0.000.00 SEQID-00945 0.04 0.03 0.03 0.04 0.07 0.00 0.05 0.08 −24.69 0.330.01 8.63 0.00 0.33 0.00 0.23 SEQID-00946 0.01 0.05 0.08 0.07 0.05 0.050.04 0.05 −19.88 0.23 −0.01 6.36 0.21 0.32 0.22 0.25 SEQID-00947 0.030.06 0.03 0.03 0.05 0.01 0.02 0.09 −17.51 0.57 0.00 6.89 0.20 0.31 0.000.20 SEQID-00948 0.03 0.05 0.06 0.05 0.07 0.00 0.02 0.08 −16.36 0.550.02 8.73 0.51 0.69 0.22 0.21 SEQID-00949 0.02 0.05 0.03 0.04 0.06 0.010.03 0.06 −22.43 0.35 −0.01 5.66 0.71 0.90 0.00 0.21 SEQID-00950 0.020.09 0.02 0.03 0.04 0.02 0.02 0.11 −19.79 0.52 0.01 7.77 0.28 0.30 0.240.25 SEQID-00951 0.03 0.06 0.04 0.05 0.04 0.03 0.05 0.06 −18.10 0.430.03 9.45 0.22 0.31 0.00 0.21 SEQID-00952 0.02 0.05 0.04 0.05 0.03 0.030.05 0.07 −22.51 0.46 −0.03 4.87 0.20 0.33 0.19 0.20 SEQID-00953 0.010.04 0.07 0.07 0.03 0.02 0.03 0.04 −23.78 0.26 −0.09 4.20 0.22 0.42 0.200.23 SEQID-00954 0.02 0.03 0.03 0.04 0.04 0.01 0.03 0.05 −25.81 0.25−0.01 5.77 0.00 0.41 0.00 0.18 SEQID-00955 0.02 0.07 0.04 0.07 0.05 0.010.03 0.08 −17.08 0.44 0.02 8.94 0.25 0.34 0.26 0.27 SEQID-00956 0.040.05 0.06 0.09 0.04 0.01 0.05 0.03 −17.66 0.20 0.02 9.66 0.24 0.41 0.260.25 SEQID-00957 0.04 0.02 0.03 0.06 0.04 0.03 0.03 0.10 −18.85 0.58−0.01 6.40 0.24 0.32 0.00 0.00 SEQID-00958 0.02 0.07 0.05 0.05 0.05 0.040.04 0.06 −18.60 0.41 0.00 7.56 0.23 0.34 0.19 0.20 SEQID-00959 0.030.05 0.04 0.04 0.07 0.01 0.03 0.06 −22.45 0.34 −0.02 5.16 0.73 0.93 0.000.22 SEQID-00960 0.01 0.04 0.12 0.06 0.02 0.01 0.04 0.08 −16.72 0.46−0.01 6.39 0.25 0.32 0.25 0.26 SEQID-00961 0.03 0.03 0.03 0.02 0.01 0.010.02 0.03 −37.46 0.14 −0.01 6.56 0.25 0.35 0.22 0.21 SEQID-00962 0.020.05 0.06 0.09 0.04 0.01 0.04 0.06 −19.01 0.20 0.02 9.32 0.21 0.35 0.190.24 SEQID-00963 0.05 0.08 0.05 0.04 0.04 0.02 0.08 0.05 −20.90 0.320.01 7.78 0.20 0.30 0.20 0.21 SEQID-00964 0.02 0.05 0.11 0.09 0.06 0.010.06 0.04 −15.14 0.27 0.01 7.95 0.20 0.45 0.20 0.21 SEQID-00965 0.040.08 0.05 0.03 0.02 0.03 0.07 0.03 −23.11 0.36 0.00 7.49 0.52 0.68 0.210.23 SEQID-00966 0.03 0.09 0.02 0.04 0.04 0.03 0.06 0.07 −16.84 0.560.07 10.36 0.21 0.34 0.00 0.00 SEQID-00967 0.03 0.04 0.03 0.05 0.04 0.020.03 0.08 −20.61 0.55 0.00 6.53 0.25 0.34 0.17 0.00 SEQID-00968 0.030.02 0.01 0.06 0.04 0.01 0.08 0.05 −25.41 0.27 −0.06 4.52 0.25 0.34 0.000.00 SEQID-00969 0.01 0.07 0.02 0.05 0.10 0.02 0.06 0.04 −18.46 0.310.01 8.89 0.21 0.31 0.00 0.00 SEQID-00970 0.03 0.06 0.04 0.04 0.05 0.010.06 0.06 −20.02 0.37 −0.05 4.69 0.94 1.00 0.20 0.22 SEQID-00971 0.020.05 0.08 0.04 0.04 0.01 0.04 0.06 −20.64 0.33 −0.02 5.02 0.27 0.56 0.210.30 SEQID-00972 0.03 0.04 0.04 0.03 0.07 0.00 0.03 0.04 −24.05 0.300.15 11.71 0.24 0.30 0.22 0.00 SEQID-00973 0.03 0.02 0.04 0.05 0.04 0.000.02 0.10 −21.20 0.60 0.00 7.44 0.20 0.33 0.00 0.23 SEQID-00974 0.030.06 0.07 0.03 0.08 0.02 0.03 0.05 −22.31 0.45 −0.01 6.30 0.50 0.56 0.000.00 SEQID-00975 0.04 0.03 0.02 0.04 0.03 0.01 0.07 0.04 −26.62 0.33−0.07 4.36 0.24 0.32 0.00 0.00 SEQID-00976 0.01 0.04 0.05 0.05 0.05 0.030.04 0.06 −20.20 0.42 0.05 9.78 0.20 0.34 0.00 0.21 SEQID-00977 0.020.04 0.03 0.06 0.05 0.02 0.05 0.06 −18.41 0.38 −0.01 6.34 0.21 0.31 0.180.22 SEQID-00978 0.01 0.05 0.07 0.04 0.03 0.03 0.02 0.06 −20.46 0.430.00 7.02 0.21 0.33 0.21 0.24 SEQID-00979 0.02 0.03 0.01 0.02 0.06 0.000.06 0.08 −23.82 0.30 0.18 11.91 0.19 0.28 0.00 0.28 SEQID-00980 0.090.09 0.01 0.03 0.06 0.00 0.01 0.04 −29.38 0.32 −0.16 3.85 0.39 0.45 0.000.25 SEQID-00981 0.02 0.01 0.03 0.04 0.03 0.00 0.03 0.06 −21.47 0.400.14 11.55 0.24 0.33 0.00 0.24 SEQID-00982 0.03 0.02 0.04 0.09 0.06 0.000.06 0.06 −23.96 0.22 0.15 11.00 0.25 0.30 0.22 0.22 SEQID-00983 0.020.10 0.05 0.05 0.04 0.02 0.04 0.05 −20.43 0.40 0.02 8.61 0.28 0.36 0.230.24 SEQID-00984 0.05 0.03 0.04 0.08 0.06 0.00 0.03 0.09 −18.31 0.470.07 10.55 0.00 0.31 0.00 0.24 SEQID-00985 0.03 0.04 0.05 0.04 0.02 0.020.08 0.05 −17.45 0.42 0.00 7.44 0.30 0.39 0.00 0.23 SEQID-00986 0.030.07 0.04 0.03 0.03 0.03 0.06 0.04 −23.98 0.30 −0.06 4.53 0.22 0.32 0.000.22 SEQID-00987 0.03 0.03 0.06 0.07 0.07 0.02 0.02 0.05 −21.44 0.230.06 10.42 0.23 0.32 0.00 0.24 SEQID-00988 0.02 0.04 0.06 0.09 0.04 0.010.04 0.10 −18.81 0.50 0.03 9.15 0.21 0.31 0.00 0.00 SEQID-00989 0.010.08 0.05 0.07 0.05 0.02 0.06 0.03 −18.71 0.25 −0.02 5.97 0.22 0.31 0.230.24 SEQID-00990 0.02 0.05 0.08 0.05 0.04 0.01 0.04 0.06 −18.94 0.320.01 8.02 0.21 0.35 0.00 0.21 SEQID-00991 0.03 0.03 0.02 0.06 0.05 0.000.08 0.05 −25.41 0.34 0.00 7.39 0.21 0.32 0.00 0.00 SEQID-00992 0.020.05 0.04 0.07 0.04 0.00 0.05 0.07 −15.67 0.41 0.02 9.07 0.21 0.34 0.000.23 SEQID-00993 0.03 0.05 0.08 0.05 0.06 0.00 0.02 0.09 −18.97 0.440.02 9.36 0.20 0.36 0.20 0.21 SEQID-00994 0.03 0.04 0.05 0.05 0.05 0.020.04 0.08 −20.80 0.41 0.03 9.50 0.22 0.34 0.00 0.22 SEQID-00995 0.040.04 0.04 0.06 0.05 0.03 0.06 0.06 −17.23 0.44 0.01 8.29 0.21 0.33 0.220.22 SEQID-00996 0.03 0.04 0.10 0.05 0.06 0.02 0.02 0.07 −17.11 0.450.01 8.25 0.21 0.36 0.22 0.22 SEQID-00997 0.04 0.05 0.02 0.05 0.05 0.000.05 0.03 −25.20 0.37 −0.02 5.65 0.19 0.34 0.00 0.20 SEQID-00998 0.020.04 0.05 0.04 0.05 0.02 0.04 0.05 −19.46 0.39 0.01 7.90 0.20 0.32 0.000.21 SEQID-00999 0.03 0.04 0.02 0.04 0.05 0.01 0.05 0.04 −28.98 0.30−0.05 4.64 0.85 0.86 0.00 0.20 SEQID-01000 0.02 0.05 0.05 0.05 0.05 0.030.04 0.06 −23.33 0.29 −0.01 5.62 0.19 0.33 0.20 0.20 SEQID-01001 0.020.05 0.03 0.05 0.05 0.02 0.04 0.07 −21.41 0.40 0.00 7.13 1.00 1.00 0.000.21 SEQID-01002 0.02 0.05 0.03 0.06 0.05 0.03 0.04 0.07 −21.00 0.420.00 7.04 0.93 1.00 0.00 0.21 SEQID-01003 0.02 0.05 0.05 0.06 0.06 0.020.05 0.06 −18.58 0.39 −0.02 5.31 0.16 0.35 0.18 0.19 SEQID-01004 0.060.08 0.03 0.07 0.07 0.02 0.05 0.05 −19.09 0.45 −0.03 4.97 0.57 0.74 0.000.45 SEQID-01005 0.02 0.04 0.02 0.06 0.04 0.07 0.03 0.04 −15.97 0.540.06 9.25 1.00 1.00 0.00 0.25 SEQID-01006 0.02 0.07 0.03 0.05 0.06 0.000.04 0.08 −20.07 0.51 −0.05 4.51 1.00 1.00 0.24 1.00 SEQID-01007 0.010.03 0.04 0.05 0.07 0.00 0.06 0.06 −20.24 0.39 −0.01 6.57 0.22 0.59 0.211.00 SEQID-01008 0.03 0.06 0.04 0.06 0.06 0.02 0.06 0.07 −17.92 0.49−0.01 5.89 0.18 0.34 0.18 0.99 SEQID-01009 0.03 0.07 0.05 0.07 0.08 0.020.06 0.08 −15.59 0.51 0.01 7.60 0.19 0.32 0.00 0.48 SEQID-01010 0.060.07 0.04 0.06 0.07 0.02 0.03 0.05 −19.62 0.48 −0.03 4.66 0.64 0.78 0.210.46 SEQID-01011 0.05 0.05 0.03 0.07 0.06 0.02 0.04 0.05 −19.80 0.440.01 8.46 0.59 0.71 0.00 0.44 SEQID-01012 0.03 0.07 0.04 0.05 0.05 0.020.01 0.05 −23.91 0.24 −0.03 5.29 0.22 0.33 0.00 0.21 SEQID-01013 0.020.03 0.08 0.06 0.05 0.03 0.02 0.10 −14.17 0.62 −0.01 6.50 0.22 0.33 0.000.23 SEQID-01014 0.01 0.07 0.02 0.06 0.08 0.00 0.00 0.06 −22.97 0.30−0.08 5.19 0.27 0.30 0.25 0.25 SEQID-01015 0.04 0.04 0.07 0.07 0.06 0.010.02 0.09 −14.50 0.66 −0.02 5.76 0.22 0.33 0.00 0.24 SEQID-01016 0.030.08 0.04 0.06 0.08 0.02 0.06 0.07 −16.56 0.51 0.01 8.22 0.20 0.34 0.000.41 SEQID-01017 0.03 0.04 0.04 0.07 0.07 0.02 0.08 0.05 −17.85 0.37−0.01 6.00 0.19 0.33 0.19 0.20 SEQID-01018 0.02 0.06 0.02 0.06 0.13 0.040.01 0.05 −16.16 0.52 0.04 10.35 0.23 0.32 0.00 0.24 SEQID-01019 0.040.04 0.03 0.10 0.04 0.04 0.05 0.02 −21.68 0.27 −0.04 4.91 0.21 0.31 0.220.21 SEQID-01020 0.05 0.04 0.02 0.06 0.07 0.02 0.06 0.07 −23.98 0.52−0.01 5.41 0.28 0.31 0.00 0.28 SEQID-01021 0.03 0.05 0.03 0.06 0.05 0.030.08 0.06 −16.96 0.39 −0.01 6.29 0.38 0.59 0.00 0.20 SEQID-01022 0.040.06 0.04 0.07 0.06 0.08 0.11 0.04 −10.42 0.83 0.11 9.33 0.31 0.25 0.360.29 SEQID-01023 0.02 0.07 0.06 0.02 0.02 0.02 0.07 0.08 −17.26 0.500.02 8.56 0.21 0.31 0.00 0.24 SEQID-01024 0.03 0.03 0.03 0.07 0.03 0.010.05 0.08 −18.61 0.64 0.01 7.82 0.24 0.30 0.24 1.00 SEQID-01025 0.010.09 0.03 0.06 0.06 0.06 0.03 0.06 −17.18 0.51 0.03 8.58 0.26 0.30 0.000.23 SEQID-01026 0.02 0.05 0.10 0.06 0.08 0.01 0.07 0.06 −14.96 0.420.00 6.78 0.98 1.00 0.00 0.24 SEQID-01027 0.03 0.05 0.04 0.06 0.08 0.010.08 0.06 −22.58 0.29 0.02 8.69 1.00 1.00 0.18 0.00 SEQID-01028 0.030.03 0.04 0.03 0.05 0.02 0.03 0.05 −20.98 0.57 −0.04 4.66 0.99 1.00 0.000.24 SEQID-01029 0.01 0.05 0.04 0.05 0.05 0.03 0.04 0.06 −19.81 0.440.02 8.38 1.00 1.00 0.00 0.21 SEQID-01030 0.03 0.07 0.05 0.05 0.06 0.010.04 0.06 −18.85 0.43 0.01 7.72 0.19 0.33 0.19 0.20 SEQID-01031 0.020.04 0.04 0.05 0.06 0.02 0.05 0.08 −21.17 0.42 0.00 6.82 0.18 0.32 0.190.24 SEQID-01032 0.02 0.07 0.04 0.05 0.08 0.04 0.05 0.04 −15.64 0.380.00 7.17 0.21 0.31 0.35 0.21 SEQID-01033 0.03 0.06 0.06 0.06 0.03 0.040.03 0.07 −21.14 0.51 −0.03 4.85 0.20 0.35 0.20 0.22 SEQID-01034 0.010.05 0.05 0.07 0.06 0.03 0.05 0.09 −19.28 0.39 0.00 7.29 0.20 0.37 0.000.21 SEQID-01035 0.02 0.06 0.05 0.05 0.08 0.04 0.03 0.05 −19.30 0.370.02 8.68 0.20 0.33 0.00 0.21 SEQID-01036 0.02 0.03 0.04 0.09 0.07 0.000.01 0.03 −22.27 0.41 −0.01 6.68 0.20 0.33 0.23 0.22 SEQID-01037 0.030.02 0.03 0.07 0.06 0.01 0.04 0.07 −19.70 0.36 −0.01 6.13 0.20 0.38 0.000.22 SEQID-01038 0.02 0.06 0.04 0.07 0.05 0.03 0.06 0.07 −19.11 0.390.02 8.68 0.21 0.45 0.00 0.22 SEQID-01039 0.02 0.05 0.04 0.06 0.06 0.030.05 0.06 −17.74 0.44 −0.05 4.44 0.21 0.32 0.20 0.22 SEQID-01040 0.020.05 0.04 0.05 0.05 0.02 0.05 0.05 −21.57 0.37 0.00 7.08 0.59 0.71 0.210.21 SEQID-01041 0.01 0.03 0.05 0.16 0.10 0.04 0.06 0.07 −12.63 0.440.00 7.74 0.18 0.31 0.22 0.23 SEQID-01042 0.01 0.07 0.06 0.11 0.07 0.040.03 0.10 −16.09 0.53 −0.03 4.64 0.22 0.34 0.00 0.21 SEQID-01043 0.010.06 0.07 0.11 0.07 0.03 0.04 0.09 −16.92 0.42 −0.02 5.16 0.22 0.35 0.190.23 SEQID-01044 0.02 0.05 0.08 0.06 0.04 0.04 0.08 0.05 −20.43 0.34−0.04 4.39 0.21 0.33 0.20 0.21 SEQID-01045 0.02 0.08 0.05 0.05 0.06 0.020.06 0.07 −17.05 0.58 0.01 8.22 0.22 0.33 0.00 0.21 SEQID-01046 0.030.04 0.05 0.03 0.03 0.01 0.02 0.04 −28.00 0.22 −0.05 4.87 0.23 0.35 0.000.23 SEQID-01047 0.02 0.06 0.06 0.06 0.02 0.02 0.06 0.04 −20.51 0.340.05 9.68 0.21 0.36 0.21 0.22 SEQID-01048 0.01 0.02 0.06 0.11 0.10 0.030.05 0.06 −15.19 0.47 −0.01 5.69 0.21 0.32 0.00 0.22 SEQID-01049 0.020.04 0.06 0.09 0.09 0.03 0.05 0.10 −17.98 0.41 0.01 7.92 0.20 0.31 0.000.23 SEQID-01050 0.02 0.05 0.02 0.06 0.06 0.04 0.08 0.04 −20.06 0.27−0.02 5.45 0.21 0.31 0.29 0.21 SEQID-01051 0.00 0.04 0.04 0.16 0.07 0.020.06 0.06 −11.96 0.30 0.01 8.20 0.22 0.31 0.27 0.28 SEQID-01052 0.020.07 0.05 0.06 0.05 0.05 0.07 0.06 −15.49 0.41 0.02 8.00 0.25 0.39 0.520.32 SEQID-01053 0.03 0.08 0.03 0.07 0.06 0.01 0.05 0.06 −15.78 0.680.02 8.87 0.19 0.31 0.20 0.20 SEQID-01054 0.03 0.05 0.05 0.06 0.05 0.020.03 0.06 −16.22 0.48 −0.01 6.42 0.17 0.35 0.17 0.19 SEQID-01055 0.010.05 0.09 0.13 0.07 0.03 0.01 0.08 −10.74 0.51 −0.01 6.21 0.22 0.31 0.200.24 SEQID-01056 0.02 0.07 0.04 0.07 0.07 0.03 0.02 0.08 −14.33 0.870.00 7.51 0.20 0.33 0.00 0.20 SEQID-01057 0.01 0.02 0.05 0.14 0.09 0.020.09 0.05 −12.66 0.22 0.01 8.03 0.24 0.34 0.29 0.23 SEQID-01058 0.040.06 0.01 0.04 0.12 0.03 0.02 0.10 −21.36 0.43 0.00 7.51 0.43 0.53 0.200.20 SEQID-01059 0.02 0.06 0.03 0.05 0.05 0.02 0.06 0.04 −22.85 0.50−0.02 5.69 0.28 0.32 0.23 0.22 SEQID-01060 0.03 0.04 0.05 0.07 0.07 0.020.02 0.05 −21.90 0.38 0.04 9.19 0.21 0.29 0.00 0.00 SEQID-01061 0.020.04 0.06 0.05 0.04 0.09 0.05 0.03 −19.03 0.26 0.02 7.89 0.21 0.31 0.200.24 SEQID-01062 0.01 0.07 0.03 0.05 0.06 0.01 0.04 0.06 −19.76 0.52−0.02 5.84 0.27 0.39 0.00 1.00 SEQID-01063 0.04 0.05 0.03 0.04 0.05 0.030.06 0.05 −21.17 0.34 −0.01 6.52 0.21 0.32 0.00 0.20 SEQID-01064 0.020.03 0.06 0.05 0.05 0.04 0.07 0.08 −19.14 0.35 0.03 8.38 0.22 0.43 0.210.26 SEQID-01065 0.02 0.08 0.05 0.07 0.04 0.04 0.03 0.06 −17.13 0.430.03 9.49 0.20 0.33 0.00 0.21 SEQID-01066 0.02 0.07 0.04 0.04 0.07 0.000.07 0.08 −14.90 0.75 0.02 8.31 0.35 0.39 0.26 0.26 SEQID-01067 0.010.05 0.06 0.07 0.01 0.03 0.07 0.05 −21.01 0.41 0.02 8.22 0.28 0.30 0.250.26 SEQID-01068 0.02 0.03 0.06 0.13 0.07 0.05 0.02 0.10 −12.39 0.590.02 8.90 0.29 0.33 0.24 0.26 SEQID-01069 0.03 0.06 0.06 0.04 0.04 0.000.06 0.05 −21.65 0.52 0.05 9.04 0.24 0.31 0.23 0.25 SEQID-01070 0.030.02 0.04 0.06 0.07 0.01 0.05 0.08 −22.47 0.46 −0.03 4.82 0.22 0.29 0.000.26 SEQID-01071 0.02 0.01 0.05 0.05 0.03 0.05 0.09 0.07 −14.44 0.450.06 9.70 0.00 0.29 0.00 0.24 SEQID-01072 0.04 0.10 0.03 0.04 0.04 0.020.04 0.06 −16.09 1.02 0.00 6.72 0.22 0.30 0.00 0.20 SEQID-01073 0.030.05 0.08 0.06 0.03 0.01 0.07 0.06 −16.32 0.42 0.04 9.51 0.21 0.32 0.000.21 SEQID-01074 0.03 0.02 0.05 0.05 0.06 0.05 0.07 0.05 −22.62 0.180.01 8.31 0.21 0.33 0.19 0.22 SEQID-01075 0.02 0.08 0.05 0.06 0.05 0.010.04 0.07 −16.97 0.49 0.00 7.11 0.21 0.33 0.00 0.22 SEQID-01076 0.010.03 0.13 0.17 0.11 0.01 0.04 0.04 −9.51 0.35 0.00 7.31 0.22 0.38 0.230.22 SEQID-01077 0.02 0.06 0.05 0.05 0.04 0.01 0.03 0.04 −19.53 0.40−0.01 6.14 1.00 1.00 0.20 0.22 SEQID-01078 0.01 0.06 0.08 0.06 0.02 0.010.03 0.04 −26.15 0.38 −0.03 4.84 1.00 1.00 0.19 0.20 SEQID-01079 0.010.06 0.05 0.06 0.02 0.01 0.03 0.04 −26.21 0.36 −0.03 5.48 0.96 1.00 0.000.20 SEQID-01080 0.01 0.04 0.08 0.06 0.03 0.02 0.04 0.05 −23.03 0.33−0.04 4.95 1.00 1.00 0.00 0.20 SEQID-01081 0.01 0.05 0.08 0.06 0.04 0.010.04 0.06 −20.74 0.36 −0.03 5.47 1.00 1.00 0.00 0.21 SEQID-01082 0.010.08 0.05 0.05 0.03 0.01 0.03 0.05 −18.72 0.42 −0.01 5.78 1.00 1.00 0.190.22 SEQID-01083 0.01 0.05 0.06 0.06 0.04 0.01 0.04 0.06 −20.28 0.34−0.02 5.75 1.00 1.00 0.00 0.22 SEQID-01084 0.02 0.09 0.04 0.06 0.04 0.010.02 0.05 −24.13 0.42 −0.01 6.47 0.45 0.63 0.00 0.21 SEQID-01085 0.020.06 0.05 0.05 0.05 0.03 0.05 0.05 −20.29 0.39 −0.01 6.55 0.20 0.33 0.000.21 SEQID-01086 0.02 0.09 0.04 0.06 0.04 0.01 0.02 0.05 −24.06 0.410.00 6.87 0.44 0.63 0.00 0.21 SEQID-01087 0.02 0.08 0.04 0.06 0.05 0.010.02 0.05 −23.27 0.45 −0.01 6.57 0.46 0.66 0.18 0.21 SEQID-01088 0.020.05 0.05 0.05 0.05 0.03 0.06 0.06 −19.35 0.40 0.00 6.73 0.20 0.34 0.000.21 SEQID-01089 0.02 0.07 0.05 0.04 0.07 0.02 0.03 0.08 −18.23 0.500.01 8.02 0.25 0.34 0.00 0.21 SEQID-01090 0.02 0.09 0.04 0.06 0.04 0.020.03 0.06 −20.83 0.56 −0.03 4.72 1.00 1.00 0.25 1.00 SEQID-01091 0.020.05 0.05 0.06 0.05 0.03 0.06 0.05 −19.29 0.37 −0.01 6.35 0.20 0.35 0.000.21 SEQID-01092 0.02 0.06 0.03 0.05 0.06 0.03 0.04 0.09 −20.78 0.500.00 7.27 0.84 0.94 0.00 0.21 SEQID-01093 0.02 0.04 0.05 0.03 0.05 0.020.05 0.07 −20.34 0.38 −0.01 6.76 0.22 0.31 0.00 0.21 SEQID-01094 0.020.06 0.03 0.05 0.06 0.03 0.04 0.11 −20.35 0.49 0.00 7.61 0.86 0.96 0.200.20 SEQID-01095 0.02 0.08 0.03 0.07 0.06 0.02 0.05 0.09 −18.22 0.570.01 7.386 0.67 0.94 0.19 0.21 SEQID-01096 0.02 0.06 0.03 0.05 0.06 0.030.04 0.10 −20.79 0.50 0.00 7.27 0.84 0.94 0.00 0.21 SEQID-01097 0.010.08 0.04 0.06 0.02 0.00 0.04 0.05 −21.37 0.48 −0.01 6.14 1.00 1.00 0.210.22 SEQID-01098 0.02 0.04 0.04 0.03 0.05 0.02 0.05 0.07 −19.99 0.38−0.01 6.76 0.21 0.31 0.00 0.20 SEQID-01099 0.01 0.04 0.05 0.04 0.10 0.010.03 0.09 −15.86 0.67 0.02 9.38 0.23 0.76 0.00 0.24 SEQID-01100 0.010.04 0.05 0.04 0.10 0.01 0.03 0.09 −16.06 0.72 0.02 9.38 0.47 0.71 0.000.21 SEQID-01101 0.01 0.07 0.05 0.05 0.02 0.00 0.03 0.04 −27.12 0.37−0.01 6.26 0.60 0.86 0.19 0.20 SEQID-01102 0.01 0.03 0.04 0.06 0.05 0.010.05 0.08 −17.38 0.42 0.01 7.63 0.21 0.32 0.00 0.22 SEQID-01103 0.030.07 0.06 0.07 0.07 0.01 0.02 0.07 −11.30 0.50 0.02 8.38 0.22 0.34 0.200.22 SEQID-01104 0.03 0.07 0.05 0.05 0.05 0.01 0.02 0.09 −18.02 0.50−0.01 6.50 0.27 0.36 0.22 0.21 SEQID-01105 0.05 0.04 0.05 0.06 0.05 0.020.06 0.07 −19.68 0.46 −0.03 5.17 0.21 0.33 0.00 0.21 SEQID-01106 0.020.07 0.05 0.04 0.06 0.02 0.03 0.08 −19.23 0.47 0.00 6.76 0.24 0.33 0.000.21 SEQID-01107 0.03 0.07 0.06 0.07 0.06 0.01 0.02 0.06 −11.25 0.480.02 8.32 0.22 0.33 0.00 0.21 SEQID-01108 0.02 0.06 0.05 0.05 0.05 0.010.03 0.10 −17.31 0.52 −0.01 6.43 0.27 0.36 0.00 0.20 SEQID-01109 0.020.05 0.04 0.06 0.06 0.03 0.05 0.07 −19.81 0.42 −0.01 6.26 0.88 0.98 0.000.21 SEQID-01110 0.01 0.07 0.05 0.10 0.08 0.04 0.03 0.07 −15.10 0.55−0.01 5.94 1.00 1.00 0.53 0.23 SEQID-01111 0.06 0.02 0.02 0.04 0.04 0.010.01 0.01 −29.45 0.31 −0.04 4.98 0.36 0.39 0.23 0.36 SEQID-01112 0.020.06 0.04 0.03 0.05 0.02 0.05 0.06 −21.45 0.41 −0.01 6.32 0.20 0.32 0.000.21 SEQID-01113 0.03 0.05 0.05 0.04 0.07 0.01 0.04 0.08 −22.27 0.400.03 9.56 0.22 0.35 0.20 0.22 SEQID-01114 0.01 0.11 0.05 0.06 0.03 0.010.04 0.07 −22.15 0.41 −0.04 4.82 0.21 0.58 0.20 0.22 SEQID-01115 0.050.04 0.05 0.05 0.06 0.02 0.06 0.06 −19.69 0.44 −0.03 5.16 0.20 0.33 0.000.21 SEQID-01116 0.02 0.04 0.03 0.04 0.05 0.02 0.05 0.09 −19.41 0.46−0.01 5.37 0.91 0.98 0.20 0.22 SEQID-01117 0.04 0.05 0.05 0.04 0.04 0.010.07 0.03 −20.78 0.29 0.00 7.07 0.22 0.29 0.00 0.00 SEQID-01118 0.030.08 0.07 0.05 0.04 0.03 0.05 0.05 −21.32 0.34 −0.01 6.11 0.22 0.37 0.000.21 SEQID-01119 0.02 0.04 0.02 0.07 0.04 0.04 0.07 0.04 −20.86 0.36−0.02 5.88 1.00 1.00 0.00 0.35 SEQID-01120 0.06 0.03 0.05 0.12 0.03 0.000.05 0.00 −23.90 0.31 −0.04 4.69 0.26 0.27 0.31 1.00 SEQID-01121 0.060.04 0.08 0.07 0.03 0.03 0.05 0.06 −20.07 0.32 −0.02 6.03 0.21 0.32 0.210.00 SEQID-01122 0.03 0.05 0.05 0.04 0.05 0.01 0.03 0.08 −16.87 0.430.00 6.85 0.25 0.34 0.24 0.00 SEQID-01123 0.02 0.05 0.04 0.08 0.06 0.020.02 0.07 −16.39 0.59 0.00 7.14 0.21 0.35 0.20 0.21 SEQID-01124 0.020.04 0.03 0.04 0.05 0.01 0.03 0.07 −25.16 0.41 −0.02 5.27 0.87 1.00 0.000.21 SEQID-01125 0.00 0.10 0.05 0.06 0.03 0.01 0.04 0.07 −21.91 0.46−0.05 4.62 0.22 0.55 0.20 0.22 SEQID-01126 0.02 0.04 0.05 0.06 0.06 0.000.04 0.08 −18.33 0.49 −0.01 6.05 0.21 0.33 0.20 0.22 SEQID-01127 0.020.08 0.04 0.05 0.05 0.02 0.04 0.07 −18.52 0.64 −0.02 4.72 1.00 1.00 0.001.00 SEQID-01128 0.03 0.03 0.05 0.05 0.05 0.03 0.03 0.09 −16.77 0.56−0.01 6.25 0.27 0.34 0.20 0.20 SEQID-01129 0.04 0.03 0.05 0.05 0.05 0.030.09 0.11 −15.32 0.61 0.00 7.46 0.27 0.34 0.00 0.23 SEQID-01130 0.020.04 0.05 0.08 0.04 0.01 0.02 0.09 −17.73 0.58 0.01 8.68 0.23 0.33 0.210.22 SEQID-01131 0.05 0.05 0.04 0.05 0.05 0.02 0.04 0.08 −21.19 0.38−0.01 5.97 0.19 0.33 0.00 0.21 SEQID-01132 0.02 0.04 0.03 0.05 0.04 0.020.05 0.08 −19.78 0.43 −0.01 6.20 0.90 0.98 0.20 0.23 SEQID-01133 0.030.06 0.04 0.05 0.05 0.01 0.06 0.08 −19.26 0.41 −0.04 4.77 0.81 0.90 0.190.22 SEQID-01134 0.05 0.07 0.04 0.05 0.05 0.02 0.05 0.06 −19.53 0.34−0.05 4.46 0.39 0.55 0.00 0.21 SEQID-01135 0.02 0.05 0.05 0.08 0.05 0.010.04 0.07 −16.45 0.48 0.01 8.66 0.21 0.34 0.22 0.22 SEQID-01136 0.030.04 0.08 0.03 0.05 0.04 0.03 0.05 −17.04 0.43 −0.03 4.88 0.21 0.31 0.200.22 SEQID-01137 0.02 0.04 0.04 0.05 0.05 0.00 0.05 0.07 −18.87 0.480.00 6.55 0.21 0.33 0.00 0.22 SEQID-01138 0.05 0.02 0.05 0.05 0.07 0.010.03 0.08 −19.52 0.52 0.01 7.63 0.22 0.34 0.00 0.22 SEQID-01139 0.030.06 0.02 0.05 0.04 0.01 0.04 0.05 −28.20 0.33 −0.05 4.66 0.67 0.83 0.000.20 SEQID-01140 0.03 0.05 0.05 0.04 0.06 0.01 0.03 0.06 −18.65 0.44−0.02 5.97 0.19 0.32 0.00 0.21 SEQID-01141 0.01 0.01 0.02 0.04 0.16 0.000.11 0.03 −18.99 0.11 −0.01 6.80 0.26 0.37 0.23 0.24 SEQID-01142 0.030.05 0.03 0.04 0.05 0.01 0.09 0.07 −23.21 0.36 −0.02 5.12 0.71 0.91 0.000.20 SEQID-01143 0.03 0.04 0.04 0.04 0.04 0.01 0.04 0.10 −22.76 0.460.05 10.21 0.23 0.30 0.00 0.19 SEQID-01144 0.03 0.05 0.05 0.05 0.06 0.000.04 0.08 −16.78 0.51 0.00 6.97 0.20 0.33 0.20 0.21 SEQID-01145 0.010.05 0.03 0.04 0.05 0.05 0.03 0.13 −17.92 0.55 0.00 6.52 0.69 0.85 0.000.23 SEQID-01146 0.07 0.01 0.02 0.04 0.02 0.01 0.01 0.00 −26.27 0.38−0.01 6.35 0.37 0.39 0.26 0.37 SEQID-01147 0.02 0.06 0.04 0.03 0.06 0.030.05 0.06 −20.17 0.37 −0.01 6.40 0.22 0.33 0.00 0.22 SEQID-01148 0.030.08 0.05 0.05 0.02 0.01 0.03 0.06 −22.38 0.28 0.13 11.03 0.24 0.29 0.190.21 SEQID-01149 0.01 0.06 0.04 0.07 0.09 0.01 0.11 0.06 −11.77 0.890.02 9.20 0.45 0.66 0.00 0.26 SEQID-01150 0.04 0.03 0.04 0.03 0.06 0.030.04 0.07 −19.34 0.53 −0.01 6.04 0.20 0.33 0.21 0.21 SEQID-01151 0.010.03 0.02 0.08 0.07 0.06 0.04 0.08 −18.83 0.44 0.01 7.81 0.21 0.30 0.000.00 SEQID-01152 0.01 0.07 0.05 0.07 0.04 0.03 0.07 0.05 −17.08 0.480.00 7.30 0.51 0.65 0.20 0.51 SEQID-01153 0.04 0.08 0.04 0.07 0.04 0.010.04 0.05 −20.47 0.46 −0.02 5.96 0.99 1.00 0.00 0.22 SEQID-01154 0.010.07 0.06 0.07 0.07 0.02 0.03 0.07 −11.40 0.52 0.02 7.89 0.40 0.52 0.000.32 SEQID-01155 0.03 0.06 0.04 0.08 0.04 0.01 0.04 0.06 −18.29 0.460.00 7.32 0.21 0.33 0.00 0.22 SEQID-01156 0.01 0.06 0.05 0.05 0.05 0.020.05 0.08 −16.00 0.53 −0.01 6.03 0.20 0.32 0.18 0.21 SEQID-01157 0.020.04 0.04 0.10 0.12 0.01 0.10 0.04 −11.42 0.75 0.02 8.90 0.28 0.66 0.210.24 SEQID-01158 0.03 0.05 0.04 0.03 0.05 0.01 0.04 0.06 −23.09 0.360.11 10.94 0.20 0.32 0.00 0.00 SEQID-01159 0.01 0.03 0.04 0.04 0.03 0.050.01 0.08 −28.74 0.19 −0.01 6.52 0.51 0.68 0.00 0.22 SEQID-01160 0.020.07 0.06 0.05 0.03 0.05 0.05 0.06 −18.96 0.36 −0.02 5.68 0.34 0.48 0.000.20 SEQID-01161 0.04 0.03 0.03 0.05 0.05 0.01 0.05 0.09 −19.80 0.480.00 7.21 0.21 0.29 0.00 0.23 SEQID-01162 0.02 0.04 0.04 0.03 0.04 0.010.03 0.04 −21.52 0.39 −0.03 6.47 0.21 0.34 0.00 0.21 SEQID-01163 0.030.04 0.03 0.07 0.04 0.01 0.06 0.04 −25.01 0.32 −0.07 4.39 0.23 0.32 0.000.00 SEQID-01164 0.02 0.06 0.05 0.05 0.04 0.00 0.03 0.06 −24.61 0.35−0.03 4.86 0.19 0.33 0.00 0.20 SEQID-01165 0.01 0.06 0.08 0.04 0.03 0.010.04 0.08 −23.84 0.38 0.12 10.90 0.00 0.31 0.00 0.23 SEQID-01166 0.020.07 0.04 0.06 0.05 0.01 0.05 0.07 −19.45 0.42 −0.02 5.20 0.20 0.34 0.000.22 SEQID-01167 0.04 0.05 0.05 0.03 0.04 0.04 0.05 0.06 −23.34 0.35−0.02 5.84 0.21 0.31 0.19 0.22 SEQID-01168 0.02 0.05 0.03 0.04 0.03 0.020.02 0.04 −32.07 0.35 −0.03 5.18 0.22 0.50 0.00 0.21 SEQID-01169 0.040.08 0.05 0.04 0.07 0.00 0.02 0.11 −24.06 0.34 0.04 10.06 0.23 0.31 0.000.20 SEQID-01170 0.02 0.10 0.06 0.06 0.03 0.03 0.00 0.09 −26.89 0.25−0.01 5.88 0.71 0.83 0.00 0.22 SEQID-01171 0.03 0.04 0.02 0.03 0.01 0.020.03 0.10 −28.78 0.34 0.14 11.14 0.26 0.34 0.23 0.23 SEQID-01172 0.030.06 0.04 0.04 0.05 0.02 0.06 0.07 −19.93 0.37 0.01 7.90 0.21 0.33 0.000.22 SEQID-01173 0.06 0.04 0.04 0.07 0.04 0.01 0.04 0.09 −17.74 0.540.00 7.20 0.19 0.32 0.00 0.23 SEQID-01174 0.02 0.04 0.03 0.02 0.02 0.010.07 0.05 −26.31 0.28 0.10 10.61 0.24 0.32 0.00 0.00 SEQID-01175 0.020.07 0.05 0.06 0.04 0.05 0.04 0.07 −18.65 0.43 0.00 6.981 0.27 0.35 0.250.25 SEQID-01176 0.03 0.03 0.05 0.07 0.03 0.03 0.03 0.08 −22.07 0.320.11 11.15 0.22 0.33 0.00 0.19 SEQID-01177 0.02 0.05 0.05 0.03 0.04 0.010.03 0.08 −19.41 0.37 0.12 11.44 0.00 0.33 0.20 0.25 SEQID-01178 0.020.06 0.04 0.05 0.04 0.03 0.05 0.06 −22.03 0.34 −0.02 5.45 0.19 0.34 0.000.20 SEQID-01179 0.02 0.06 0.04 0.06 0.04 0.02 0.02 0.06 −19.17 0.54−0.02 5.11 0.20 0.35 0.00 0.23 SEQID-01180 0.01 0.04 0.04 0.09 0.05 0.020.05 0.07 −19.10 0.38 0.00 6.53 0.22 0.34 0.21 0.21 SEQID-01181 0.010.05 0.04 0.10 0.05 0.02 0.04 0.07 −15.33 0.56 0.01 7.73 0.21 0.33 0.000.23 SEQID-01182 0.04 0.05 0.05 0.05 0.06 0.03 0.05 0.04 −23.47 0.27−0.01 6.04 0.21 0.31 0.00 0.20 SEQID-01183 0.01 0.05 0.06 0.04 0.04 0.050.06 0.04 −29.60 0.23 −0.11 4.19 0.37 0.55 0.00 0.22 SEQID-01184 0.020.04 0.06 0.06 0.06 0.01 0.06 0.09 −11.24 1.01 0.03 9.70 0.72 0.88 0.000.26 SEQID-01185 0.03 0.07 0.05 0.06 0.04 0.03 0.00 0.09 −25.30 0.280.00 6.382 0.73 0.84 0.00 0.21 SEQID-01186 0.02 0.06 0.04 0.03 0.07 0.020.02 0.08 −22.51 0.39 0.09 11.06 0.20 0.33 0.00 0.25 SEQID-01187 0.040.06 0.03 0.04 0.06 0.01 0.04 0.08 −20.50 0.45 −0.02 5.09 0.21 0.33 0.000.00 SEQID-01188 0.02 0.05 0.03 0.03 0.06 0.02 0.05 0.08 −24.54 0.310.12 10.75 0.68 0.79 0.00 0.00 SEQID-01189 0.01 0.07 0.06 0.07 0.03 0.040.08 0.06 −18.06 0.47 −0.03 5.52 0.43 0.61 0.21 0.21 SEQID-01190 0.020.04 0.03 0.03 0.04 0.00 0.09 0.06 −27.23 0.36 0.04 9.73 0.19 0.31 0.000.00 SEQID-01191 0.02 0.07 0.06 0.06 0.06 0.02 0.07 0.08 −11.49 1.060.03 9.41 0.37 0.50 0.23 0.27 SEQID-01192 0.01 0.07 0.04 0.06 0.06 0.030.06 0.08 −20.15 0.37 0.01 8.19 0.17 0.32 0.00 0.00 SEQID-01193 0.020.07 0.04 0.05 0.06 0.01 0.04 0.04 −21.17 0.30 0.17 11.45 0.23 0.31 0.200.22 SEQID-01194 0.04 0.05 0.02 0.06 0.05 0.06 0.04 0.05 −21.04 0.43−0.03 5.03 0.00 0.32 0.00 0.21 SEQID-01195 0.04 0.06 0.02 0.04 0.02 0.010.06 0.10 −21.65 0.54 0.07 10.46 0.00 0.31 0.24 0.24 SEQID-01196 0.010.07 0.06 0.07 0.04 0.03 0.04 0.09 −15.53 0.59 0.01 8.47 0.47 0.64 0.180.47 SEQID-01197 0.01 0.04 0.04 0.06 0.04 0.01 0.04 0.05 −24.61 0.220.12 10.98 0.21 0.30 0.00 0.21 SEQID-01198 0.03 0.06 0.02 0.05 0.03 0.010.06 0.08 −23.27 0.36 0.08 10.54 0.21 0.32 0.00 0.25 SEQID-01199 0.010.09 0.03 0.05 0.04 0.01 0.05 0.06 −20.99 0.33 0.00 7.18 0.23 0.32 0.250.25 SEQID-01200 0.03 0.04 0.04 0.05 0.05 0.02 0.03 0.07 −25.01 0.35−0.07 4.28 0.37 0.58 0.00 0.00 SEQID-01201 0.04 0.04 0.01 0.03 0.04 0.020.03 0.07 −25.72 0.31 0.13 11.26 0.25 0.31 0.22 0.21 SEQID-01202 0.050.07 0.03 0.04 0.05 0.04 0.05 0.08 −17.45 0.56 0.00 6.68 0.00 0.33 0.000.20 SEQID-01203 0.03 0.05 0.03 0.05 0.06 0.02 0.07 0.07 −19.45 0.37−0.01 5.34 0.22 0.33 0.00 0.21 SEQID-01204 0.03 0.03 0.03 0.07 0.05 0.010.09 0.12 −27.72 0.21 0.16 11.65 0.24 0.29 0.00 0.23 SEQID-01205 0.030.03 0.03 0.06 0.07 0.01 0.07 0.04 −20.53 0.39 0.03 9.09 0.22 0.32 0.000.00 SEQID-01206 0.02 0.05 0.01 0.06 0.04 0.01 0.03 0.08 −24.54 0.330.05 10.05 0.00 0.31 0.00 0.24 SEQID-01207 0.02 0.07 0.07 0.08 0.09 0.010.04 0.07 −12.03 0.56 0.02 8.63 0.39 0.57 0.19 0.22 SEQID-01208 0.020.05 0.05 0.06 0.04 0.02 0.04 0.08 −21.37 0.38 0.00 6.41 0.19 0.33 0.000.21 SEQID-01209 0.02 0.06 0.08 0.07 0.04 0.04 0.05 0.06 −18.32 0.37−0.03 5.77 0.21 0.34 0.00 0.22 SEQID-01210 0.04 0.02 0.02 0.04 0.05 0.000.02 0.09 −21.67 0.55 −0.01 6.45 0.21 0.34 0.00 0.21 SEQID-01211 0.020.12 0.02 0.03 0.04 0.00 0.00 0.05 −21.54 0.57 0.11 9.35 0.28 0.26 0.320.29 SEQID-01212 0.03 0.04 0.05 0.06 0.05 0.00 0.04 0.10 −16.48 0.540.01 8.30 0.53 0.74 0.00 0.23 SEQID-01213 0.03 0.05 0.07 0.04 0.06 0.020.04 0.06 −21.02 0.30 0.00 6.94 0.71 0.81 0.00 0.22 SEQID-01214 0.020.06 0.04 0.02 0.07 0.01 0.09 0.08 −22.28 0.35 −0.01 5.81 0.78 0.88 0.000.21 SEQID-01215 0.02 0.05 0.04 0.06 0.08 0.01 0.03 0.08 −20.11 0.520.00 7.40 0.21 0.31 0.00 0.21 SEQID-01216 0.03 0.04 0.04 0.06 0.05 0.010.02 0.09 −18.22 0.67 0.00 6.95 0.21 0.36 0.20 0.22 SEQID-01217 0.020.06 0.02 0.07 0.04 0.02 0.04 0.05 −28.13 0.27 −0.05 4.64 0.43 0.69 0.000.20 SEQID-01218 0.04 0.08 0.05 0.11 0.09 0.01 0.02 0.07 −13.96 0.430.03 9.02 0.20 0.96 0.00 0.21 SEQID-01219 0.05 0.02 0.03 0.07 0.08 0.020.02 0.09 −19.87 0.53 −0.01 6.56 0.20 0.37 0.17 0.00 SEQID-01220 0.030.06 0.05 0.04 0.05 0.03 0.04 0.08 −18.51 0.48 0.00 7.07 0.21 0.34 0.000.20 SEQID-01221 0.01 0.04 0.03 0.05 0.04 0.01 0.03 0.05 −27.59 0.240.16 11.39 0.21 0.34 0.22 0.00 SEQID-01222 0.03 0.04 0.04 0.05 0.07 0.000.01 0.06 −23.57 0.34 0.09 11.50 0.22 0.29 0.18 0.22 SEQID-01223 0.030.04 0.04 0.07 0.04 0.02 0.06 0.06 −21.05 0.28 0.10 10.83 0.22 0.28 0.000.20 SEQID-01224 0.05 0.05 0.03 0.05 0.02 0.02 0.03 0.07 −22.77 0.400.09 10.51 0.22 0.30 0.00 0.21 SEQID-01225 0.01 0.01 0.07 0.03 0.03 0.000.04 0.08 −21.61 0.44 0.15 11.36 0.26 0.30 0.00 0.27 SEQID-01226 0.020.07 0.04 0.05 0.04 0.01 0.02 0.09 −20.11 0.58 −0.02 5.28 0.40 0.48 0.240.00 SEQID-01227 0.05 0.07 0.08 0.04 0.03 0.00 0.09 0.06 −22.82 0.400.10 11.11 0.00 0.29 0.00 0.23 SEQID-01228 0.07 0.04 0.03 0.05 0.02 0.000.06 0.08 −18.17 0.45 −0.02 6.08 0.26 0.30 0.24 0.24 SEQID-01229 0.030.01 0.05 0.04 0.07 0.01 0.02 0.09 −24.32 0.28 0.06 10.25 0.21 0.33 0.000.24 SEQID-01230 0.02 0.05 0.04 0.04 0.04 0.00 0.05 0.09 −27.23 0.330.07 10.42 0.20 0.32 0.00 0.22 SEQID-01231 0.01 0.06 0.04 0.03 0.02 0.000.06 0.06 −21.84 0.51 0.12 10.79 0.23 0.32 0.00 0.00 SEQID-01232 0.030.05 0.06 0.04 0.06 0.01 0.04 0.06 −20.35 0.32 0.01 8.31 0.20 0.32 0.000.22 SEQID-01233 0.03 0.05 0.02 0.04 0.05 0.02 0.03 0.07 −25.82 0.250.08 10.50 0.20 0.30 0.00 0.00 SEQID-01234 0.02 0.02 0.06 0.05 0.05 0.010.00 0.11 −23.74 0.48 0.03 9.63 0.20 0.32 0.00 0.25 SEQID-01235 0.020.10 0.10 0.03 0.03 0.02 0.07 0.02 −20.74 0.19 0.05 10.10 0.29 0.45 0.000.29 SEQID-01236 0.02 0.03 0.05 0.07 0.05 0.03 0.05 0.07 −16.99 0.430.00 6.77 0.22 0.34 0.00 0.21 SEQID-01237 0.01 0.06 0.06 0.05 0.02 0.040.05 0.04 −26.99 0.40 −0.06 4.51 0.41 0.71 0.00 0.22 SEQID-01238 0.030.04 0.04 0.06 0.05 0.02 0.05 0.07 −20.81 0.36 0.00 7.00 0.22 0.31 0.220.22 SEQID-01239 0.06 0.04 0.05 0.04 0.08 0.01 0.02 0.08 −9.86 0.97 0.028.55 0.42 0.55 0.00 0.23 SEQID-01240 0.03 0.04 0.03 0.06 0.06 0.02 0.070.09 −15.50 0.47 −0.02 5.23 0.22 0.35 0.00 0.23 SEQID-01241 0.03 0.050.04 0.05 0.05 0.01 0.06 0.07 −19.27 0.43 0.00 6.91 0.20 0.31 0.19 0.20SEQID-01242 0.02 0.07 0.07 0.09 0.07 0.01 0.06 0.08 −12.30 0.51 0.018.06 0.37 0.55 0.00 0.22 SEQID-01243 0.04 0.05 0.05 0.05 0.06 0.02 0.060.07 −19.43 0.38 −0.02 5.16 0.21 0.33 0.00 0.21 SEQID-01244 0.01 0.060.08 0.06 0.05 0.03 0.04 0.06 −16.02 0.43 −0.01 6.23 0.22 0.34 0.22 0.23SEQID-01245 0.01 0.04 0.02 0.06 0.09 0.02 0.03 0.04 −16.05 0.52 0.006.94 0.23 0.32 0.00 0.24 SEQID-01246 0.00 0.08 0.02 0.05 0.02 0.02 0.090.05 −27.51 0.35 0.05 10.27 0.21 0.34 0.00 0.19 SEQID-01247 0.02 0.010.01 0.04 0.07 0.00 0.06 0.05 −31.20 0.10 0.00 6.28 0.22 0.36 0.23 0.22SEQID-01248 0.01 0.06 0.07 0.06 0.04 0.03 0.04 0.10 −19.05 0.58 −0.016.40 0.29 0.39 0.00 0.22 SEQID-01249 0.03 0.05 0.04 0.11 0.04 0.02 0.040.06 −16.73 0.49 0.01 9.15 0.23 0.32 0.00 0.21 SEQID-01250 0.04 0.090.03 0.06 0.03 0.00 0.01 0.07 −25.26 0.42 −0.08 4.21 0.27 0.36 0.24 0.26SEQID-01251 0.02 0.07 0.04 0.05 0.05 0.02 0.04 0.07 −18.30 0.43 0.007.16 0.51 0.78 0.20 0.23 SEQID-01252 0.03 0.04 0.03 0.04 0.04 0.02 0.060.06 −20.96 0.44 −0.01 5.63 0.21 0.33 0.21 0.22 SEQID-01253 0.02 0.070.06 0.06 0.05 0.04 0.09 0.05 −14.18 0.42 −0.03 4.68 0.36 0.59 0.00 0.18SEQID-01254 0.02 0.01 0.05 0.07 0.11 0.00 0.03 0.04 −20.46 0.18 0.039.81 0.35 0.57 0.22 0.25 SEQID-01255 0.03 0.06 0.05 0.03 0.04 0.04 0.080.07 −18.03 0.39 −0.02 5.40 0.20 0.32 0.00 0.19 SEQID-01256 0.01 0.060.04 0.05 0.04 0.01 0.03 0.08 −21.42 0.48 0.00 7.81 0.22 0.34 0.20 0.20SEQID-01257 0.03 0.04 0.03 0.06 0.07 0.02 0.05 0.10 −19.33 0.45 0.006.96 0.87 0.90 0.00 0.22 SEQID-01258 0.03 0.04 0.04 0.04 0.07 0.00 0.040.09 −20.05 0.47 0.00 7.78 0.21 0.31 0.19 0.21 SEQID-01259 0.03 0.050.03 0.06 0.06 0.02 0.05 0.10 −19.34 0.46 0.00 6.96 0.67 0.90 0.23 0.00SEQID-01260 0.02 0.06 0.04 0.05 0.07 0.00 0.02 0.06 −22.84 0.34 −0.034.73 0.76 0.93 0.19 0.21 SEQID-01261 0.03 0.04 0.04 0.06 0.07 0.02 0.050.10 −19.20 0.47 0.01 8.57 0.67 0.90 0.00 0.00 SEQID-01262 0.02 0.060.04 0.05 0.07 0.00 0.02 0.06 −22.96 0.34 −0.03 4.68 0.77 0.93 0.19 0.21SEQID-01263 0.00 0.06 0.03 0.05 0.05 0.02 0.04 0.10 −20.31 0.47 −0.015.81 0.50 0.60 0.00 0.23 SEQID-01264 0.02 0.05 0.04 0.04 0.06 0.02 0.030.09 −21.72 0.43 0.03 9.58 0.22 0.34 0.00 0.21 SEQID-01265 0.03 0.060.04 0.04 0.07 0.02 0.05 0.06 −16.92 0.48 −0.01 6.11 0.21 0.33 0.00 0.22SEQID-01266 0.02 0.03 0.02 0.06 0.02 0.00 0.06 0.06 −29.53 0.07 −0.035.00 0.29 0.33 0.00 0.26 SEQID-01267 0.03 0.06 0.04 0.04 0.05 0.01 0.060.06 −20.53 0.36 −0.03 5.59 0.21 0.31 0.00 0.21 SEQID-01268 0.01 0.070.04 0.05 0.05 0.02 0.05 0.07 −21.13 0.39 −0.01 6.41 0.47 0.79 0.00 0.20SEQID-01269 0.02 0.04 0.03 0.04 0.04 0.00 0.04 0.05 −24.71 0.37 −0.025.10 0.19 0.35 0.35 0.20 SEQID-01270 0.02 0.06 0.03 0.05 0.05 0.01 0.040.05 −27.58 0.30 −0.06 4.48 0.76 0.89 0.00 0.20 SEQID-01271 0.03 0.060.04 0.04 0.05 0.02 0.03 0.09 −21.10 0.46 −0.01 6.23 0.19 0.32 0.00 0.20SEQID-01272 0.02 0.02 0.05 0.11 0.09 0.00 0.05 0.04 −22.42 0.06 −0.026.36 0.18 0.34 0.19 0.20 SEQID-01273 0.02 0.02 0.02 0.09 0.05 0.01 0.060.04 −23.40 0.25 −0.05 4.54 0.21 0.37 0.00 0.00 SEQID-01274 0.02 0.060.03 0.05 0.05 0.01 0.04 0.05 −27.83 0.30 −0.05 4.54 0.75 0.89 0.00 0.21SEQID-01275 0.01 0.05 0.02 0.05 0.07 0.01 0.06 0.01 −25.21 0.03 −0.074.34 0.27 0.33 0.23 0.22 SEQID-01276 0.02 0.06 0.04 0.06 0.05 0.02 0.050.07 −18.75 0.39 0.00 6.72 0.54 0.69 0.18 0.22 SEQID-01277 0.01 0.030.06 0.05 0.03 0.03 0.05 0.06 −22.75 0.33 0.02 9.34 0.20 0.38 0.00 0.00SEQID-01278 0.02 0.05 0.03 0.04 0.06 0.03 0.04 0.08 −23.46 0.33 0.1110.96 0.76 0.36 0.00 0.16 SEQID-01279 0.01 0.08 0.04 0.05 0.05 0.02 0.070.07 −17.43 0.40 −0.01 6.41 0.22 0.33 0.22 0.22 SEQID-01280 0.03 0.050.04 0.05 0.07 0.01 0.04 0.06 −20.24 0.42 −0.02 6.13 0.22 0.33 0.00 0.21SEQID-01281 0.02 0.09 0.04 0.06 0.05 0.05 0.06 0.03 −23.17 0.27 −0.025.44 0.21 0.33 0.00 0.20 SEQID-01282 0.02 0.03 0.04 0.06 0.04 0.01 0.050.06 −25.53 0.22 −0.08 4.34 0.21 0.35 0.00 0.21 SEQID-01283 0.01 0.040.03 0.06 0.05 0.01 0.04 0.07 −18.54 0.48 0.01 9.50 0.22 0.36 0.21 0.22SEQID-01284 0.02 0.06 0.03 0.06 0.07 0.00 0.02 0.08 −21.88 0.41 −0.025.08 0.59 0.81 0.00 0.21 SEQID-01285 0.01 0.01 0.00 0.05 0.03 0.02 0.010.03 −37.09 0.07 −0.12 4.28 0.28 0.40 0.27 0.25 SEQID-01286 0.05 0.050.04 0.06 0.05 0.02 0.05 0.06 −19.01 0.47 −0.02 5.43 0.20 0.30 0.00 0.20SEQID-01287 0.02 0.08 0.03 0.05 0.07 0.03 0.04 0.06 −17.74 0.39 −0.016.43 0.20 0.34 0.00 0.20 SEQID-01288 0.02 0.06 0.03 0.05 0.08 0.00 0.030.05 −22.82 0.33 −0.03 4.79 0.74 0.93 0.21 0.21 SEQID-01289 0.02 0.050.05 0.04 0.06 0.02 0.04 0.05 −20.52 0.37 0.01 8.25 0.19 0.33 0.00 0.21SEQID-01290 0.03 0.05 0.04 0.06 0.05 0.02 0.06 0.07 −20.89 0.37 −0.016.05 0.20 0.33 0.20 0.19 SEQID-01291 0.02 0.03 0.04 0.05 0.06 0.00 0.020.08 −21.70 0.46 −0.02 4.95 0.21 0.32 0.20 0.22 SEQID-01292 0.03 0.050.04 0.04 0.07 0.02 0.05 0.07 −17.32 0.48 −0.01 6.40 0.20 0.32 0.00 0.21SEQID-01293 0.01 0.08 0.05 0.05 0.05 0.02 0.08 0.06 −20.30 0.23 −0.016.51 0.30 0.50 0.00 0.21 SEQID-01294 0.02 0.05 0.03 0.05 0.04 0.03 0.040.08 −18.83 0.47 −0.03 5.16 0.21 0.31 0.00 0.21 SEQID-01295 0.03 0.050.05 0.04 0.05 0.01 0.05 0.05 −21.84 0.41 −0.02 5.10 0.21 0.33 0.00 0.22SEQID-01296 0.03 0.04 0.04 0.06 0.06 0.02 0.05 0.06 −18.84 0.41 0.006.65 0.20 0.32 0.00 0.20 SEQID-01297 0.01 0.05 0.04 0.02 0.05 0.01 0.050.08 −23.48 0.33 0.09 10.73 0.19 0.33 0.00 0.00 SEQID-01298 0.01 0.030.04 0.07 0.04 0.01 0.05 0.03 −26.76 0.21 −0.09 4.26 0.22 0.33 0.00 0.24SEQID-01299 0.02 0.05 0.04 0.04 0.07 0.00 0.03 0.08 −18.91 0.51 −0.015.41 0.22 0.35 0.20 0.22 SEQID-01300 0.02 0.05 0.03 0.06 0.06 0.02 0.030.07 −20.35 0.44 −0.01 6.35 0.19 0.34 0.19 0.20 SEQID-01301 0.03 0.050.04 0.05 0.05 0.02 0.03 0.06 −22.18 0.42 −0.01 5.91 0.20 0.34 0.19 0.19SEQID-01302 0.03 0.05 0.04 0.04 0.05 0.01 0.04 0.08 −20.21 0.40 −0.016.15 0.19 0.33 0.20 0.20 SEQID-01303 0.06 0.05 0.03 0.07 0.06 0.00 0.020.06 −23.96 0.40 −0.06 4.56 0.26 0.29 0.00 0.00 SEQID-01304 0.02 0.060.04 0.04 0.02 0.01 0.06 0.06 −24.23 0.28 0.10 10.63 0.23 0.32 0.00 0.00SEQID-01305 0.02 0.03 0.04 0.06 0.04 0.03 0.06 0.09 −16.90 0.51 0.006.73 0.73 0.30 0.00 0.21 SEQID-01306 0.04 0.06 0.03 0.04 0.06 0.00 0.040.07 −21.66 0.45 −0.03 4.75 0.22 0.31 0.00 0.19 SEQID-01307 0.01 0.020.00 0.21 0.00 0.00 0.15 0.01 −21.89 0.01 −0.06 4.06 0.23 0.43 0.23 0.26SEQID-01308 0.01 0.06 0.04 0.09 0.08 0.03 0.05 0.06 −20.01 0.29 −0.035.00 0.21 0.33 0.00 0.22 SEQID-01309 0.02 0.05 0.03 0.05 0.05 0.00 0.040.07 −21.77 0.36 −0.01 6.25 0.22 0.34 0.20 0.21 SEQID-01310 0.02 0.050.03 0.07 0.04 0.02 0.06 0.07 −18.68 0.38 −0.01 5.39 0.22 0.33 0.22 0.22SEQID-01311 0.03 0.04 0.04 0.05 0.05 0.01 0.07 0.06 −195.91 0.35 0.017.47 0.21 0.33 0.00 0.21 SEQID-01312 0.01 0.05 0.04 0.06 0.05 0.02 0.060.05 −20.58 0.42 0.01 8.65 0.22 0.34 0.00 0.22 SEQID-01313 0.03 0.060.04 0.05 0.04 0.03 0.05 0.05 −19.18 0.46 0.00 6.60 0.21 0.33 0.00 0.22SEQID-01314 0.01 0.06 0.04 0.05 0.07 0.02 0.05 0.07 −17.18 0.47 −0.016.11 0.21 0.33 0.00 0.22 SEQID-01315 0.02 0.06 0.04 0.07 0.05 0.02 0.060.06 −19.03 0.36 −0.01 6.05 0.19 0.34 0.00 0.20 SEQID-01316 0.02 0.070.05 0.06 0.08 0.02 0.04 0.07 −19.19 0.43 −0.01 5.73 0.18 0.35 0.18 0.19SEQID-01317 0.01 0.07 0.04 0.04 0.07 0.01 0.06 0.09 −19.96 0.34 0.1711.44 0.23 0.30 0.00 0.22 SEQID-01318 0.01 0.07 0.06 0.06 0.03 0.02 0.050.07 −23.65 0.27 −0.02 5.15 0.00 0.45 0.00 0.00 SEQID-01319 0.02 0.040.03 0.03 0.06 0.01 0.02 0.09 −22.45 0.39 0.01 9.04 0.22 0.31 0.00 0.00SEQID-01320 0.01 0.08 0.03 0.06 0.04 0.01 0.01 0.05 −29.34 0.21 −0.074.40 0.22 0.32 0.00 0.00 SEQID-01321 0.02 0.06 0.02 0.05 0.06 0.01 0.010.08 −24.62 0.30 0.08 10.75 0.24 0.32 0.00 0.00 SEQID-01322 0.02 0.060.02 0.05 0.06 0.01 0.01 0.09 −24.64 0.30 0.08 10.78 0.00 0.30 0.00 0.00SEQID-01323 0.03 0.04 0.02 0.07 0.07 0.06 0.03 0.07 −17.42 0.43 −0.016.16 0.22 0.36 0.21 0.00 SEQID-01324 0.01 0.06 0.03 0.06 0.06 0.01 0.050.07 −22.79 0.46 0.00 6.33 0.20 0.30 0.21 0.20 SEQID-01325 0.02 0.050.03 0.06 0.07 0.00 0.02 0.08 −21.39 0.39 −0.01 5.24 0.49 0.78 0.00 0.22SEQID-01326 0.02 0.05 0.03 0.06 0.05 0.04 0.05 0.06 −21.70 0.31 0.018.29 0.19 0.33 0.00 0.20 SEQID-01327 0.01 0.05 0.04 0.04 0.04 0.01 0.040.08 −24.49 0.38 0.11 10.81 0.22 0.33 0.00 0.27 SEQID-01328 0.01 0.040.06 0.04 0.07 0.02 0.02 0.08 −18.01 0.47 0.08 11.13 0.22 0.33 0.19 0.20SEQID-01329 0.03 0.04 0.04 0.03 0.05 0.00 0.04 0.09 −22.67 0.45 0.039.94 0.23 0.34 0.00 0.00 SEQID-01330 0.02 0.07 0.04 0.06 0.04 0.01 0.040.10 −19.25 0.55 −0.05 4.46 0.00 0.45 0.00 0.21 SEQID-01331 0.01 0.050.05 0.06 0.04 0.02 0.06 0.07 −19.89 0.43 −0.01 6.52 0.20 0.34 0.00 0.21SEQID-01332 0.01 0.00 0.02 0.07 0.02 0.02 0.08 0.07 −23.86 0.20 −0.015.85 0.27 0.29 0.00 0.26 SEQID-01333 0.01 0.09 0.04 0.04 0.04 0.01 0.040.11 −24.55 0.35 0.16 11.08 0.22 0.31 0.25 0.00 SEQID-01334 0.05 0.070.03 0.03 0.04 0.02 0.06 0.08 −24.22 0.34 −0.09 4.17 0.56 0.61 0.00 0.00SEQID-01335 0.01 0.05 0.04 0.02 0.04 0.01 0.02 0.06 −25.90 0.30 0.1411.76 0.23 0.31 0.00 0.26 SEQID-01336 0.01 0.03 0.04 0.06 0.07 0.03 0.090.09 −18.37 0.41 0.10 11.33 0.20 0.33 0.00 0.21 SEQID-01337 0.03 0.050.03 0.04 0.07 0.02 0.06 0.06 −22.66 0.39 −0.01 6.08 0.22 0.32 0.00 0.21SEQID-01338 0.03 0.05 0.05 0.05 0.05 0.00 0.05 0.05 −22.25 0.33 −0.044.69 0.21 0.32 0.18 0.21 SEQID-01339 0.03 0.05 0.05 0.06 0.06 0.02 0.060.05 −18.50 0.38 −0.01 6.31 0.20 0.31 0.20 0.21 SEQID-01340 0.02 0.070.04 0.05 0.05 0.02 0.07 0.05 −20.27 0.36 0.00 6.59 0.23 0.35 0.19 0.22SEQID-01341 0.02 0.06 0.05 0.07 0.05 0.02 0.06 0.06 −17.18 0.38 0.007.01 0.20 0.33 0.19 0.21 SEQID-01342 0.01 0.06 0.04 0.06 0.04 0.00 0.060.09 −21.26 0.41 0.12 10.91 0.21 0.29 0.19 0.00 SEQID-01343 0.01 0.030.02 0.04 0.06 0.00 0.06 0.07 −25.42 0.31 0.13 10.52 0.23 0.35 0.23 0.27SEQID-01344 0.03 0.07 0.03 0.05 0.04 0.02 0.07 0.07 −23.79 0.20 0.1310.92 0.00 0.31 0.00 0.22 SEQID-01345 0.01 0.07 0.05 0.03 0.06 0.03 0.040.08 −19.47 0.58 −0.03 4.77 0.29 0.37 0.00 0.24 SEQID-01346 0.01 0.030.04 0.05 0.04 0.01 0.04 0.07 −20.01 0.36 0.12 11.68 0.23 0.34 0.22 0.00SEQID-01347 0.01 0.04 0.06 0.03 0.05 0.03 0.04 0.08 −20.44 0.47 −0.064.40 0.00 0.33 0.00 0.00 SEQID-01348 0.01 0.06 0.04 0.08 0.07 0.01 0.040.09 −18.50 0.53 0.00 7.71 0.22 0.32 0.00 0.00 SEQID-01349 0.02 0.050.05 0.04 0.04 0.01 0.05 0.07 −20.33 0.50 −0.01 6.12 0.23 0.36 0.00 0.22SEQID-01350 0.02 0.05 0.04 0.05 0.06 0.02 0.06 0.06 −21.78 0.39 −0.034.98 0.23 0.31 0.00 0.21 SEQID-01351 0.02 0.05 0.04 0.04 0.08 0.03 0.070.05 −20.92 0.30 0.02 9.42 0.22 0.31 0.00 0.22 SEQID-01352 0.01 0.060.05 0.03 0.04 0.03 0.07 0.05 −20.99 0.27 −0.01 6.53 0.22 0.31 0.00 0.21SEQID-01353 0.03 0.05 0.03 0.04 0.04 0.02 0.04 0.07 −18.95 0.51 −0.026.20 0.22 0.36 0.00 0.21 SEQID-01354 0.02 0.06 0.03 0.06 0.05 0.03 0.060.08 −18.88 0.42 −0.02 6.00 0.20 0.32 0.00 0.21 SEQID-01355 0.02 0.080.04 0.05 0.03 0.01 0.06 0.07 −22.02 0.40 −0.09 4.13 0.26 0.51 0.00 0.22SEQID-01356 0.02 0.06 0.04 0.04 0.04 0.00 0.05 0.05 −25.30 0.31 −0.016.53 0.22 0.35 0.20 0.23 SEQID-01357 0.03 0.01 0.01 0.04 0.05 0.02 0.000.15 −22.84 0.58 −0.07 4.39 0.23 0.31 0.00 0.24 SEQID-01358 0.02 0.100.06 0.05 0.05 0.01 0.05 0.09 −17.80 0.34 0.01 7.57 0.73 0.90 0.00 0.26SEQID-01359 0.01 0.01 0.01 0.04 0.03 0.02 0.03 0.06 −28.98 0.20 0.1811.91 0.25 0.31 0.00 0.22 SEQID-01360 0.01 0.05 0.02 0.07 0.05 0.02 0.040.04 −24.31 0.18 0.14 11.33 0.18 0.29 0.00 0.21 SEQID-01361 0.01 0.060.05 0.05 0.04 0.00 0.02 0.08 −22.96 0.37 0.06 10.53 0.19 0.30 0.00 0.24SEQID-01362 0.01 0.05 0.04 0.04 0.03 0.01 0.06 0.05 −21.23 0.30 0.1010.79 0.21 0.33 0.20 0.20 SEQID-01363 0.01 0.04 0.05 0.03 0.05 0.01 0.050.07 −22.07 0.39 0.10 10.72 0.23 0.33 0.18 0.00 SEQID-01364 0.01 0.100.03 0.04 0.05 0.01 0.05 0.05 −23.63 0.37 −0.03 4.88 0.00 0.32 0.00 0.00SEQID-01365 0.01 0.05 0.06 0.04 0.08 0.03 0.06 0.04 −22.68 0.28 −0.025.25 0.18 0.32 0.00 0.00 SEQID-01366 0.04 0.09 0.03 0.06 0.04 0.02 0.060.06 −16.35 0.58 0.06 10.33 0.21 0.32 0.00 0.00 SEQID-01367 0.01 0.060.03 0.04 0.06 0.01 0.08 0.04 −24.70 0.29 0.00 6.81 0.22 0.33 0.00 0.23SEQID-01368 0.02 0.05 0.05 0.06 0.05 0.00 0.01 0.08 −19.00 0.47 0.018.96 0.58 0.76 0.00 0.18 SEQID-01369 0.00 0.07 0.03 0.07 0.05 0.00 0.060.08 −20.78 0.37 0.00 8.30 0.00 0.35 0.00 0.25 SEQID-01370 0.01 0.050.04 0.06 0.07 0.01 0.04 0.07 −17.38 0.42 −0.01 6.51 0.23 0.32 0.00 0.00SEQID-01371 0.02 0.04 0.04 0.06 0.06 0.02 0.07 0.06 −20.40 0.42 −0.024.87 0.21 0.34 0.20 0.22 SEQID-01372 0.02 0.06 0.03 0.08 0.05 0.03 0.030.07 −17.92 0.37 0.00 7.35 0.21 0.34 0.00 0.23 SEQID-01373 0.03 0.060.04 0.05 0.04 0.03 0.05 0.05 −19.21 0.48 0.00 7.32 0.20 0.33 0.21 0.22SEQID-01374 0.03 0.06 0.04 0.04 0.07 0.01 0.05 0.07 −19.45 0.41 −0.025.08 0.49 0.60 0.00 0.22 SEQID-01375 0.02 0.06 0.04 0.06 0.05 0.01 0.030.06 −20.98 0.35 0.01 7.50 0.21 0.31 0.20 0.23 SEQID-01376 0.03 0.060.04 0.05 0.06 0.02 0.05 0.07 −18.69 0.42 0.01 8.01 0.20 0.32 0.00 0.21SEQID-01377 0.03 0.05 0.04 0.06 0.05 0.02 0.04 0.06 −20.70 0.39 −0.025.11 0.18 0.37 0.18 0.19 SEQID-01378 0.01 0.05 0.04 0.07 0.11 0.00 0.020.08 −16.90 0.49 0.08 9.51 0.29 0.29 0.28 0.29 SEQID-01379 0.01 0.070.02 0.04 0.03 0.00 0.04 0.10 −26.89 0.28 0.14 11.20 0.24 0.32 0.00 0.21SEQID-01380 0.03 0.05 0.02 0.05 0.03 0.01 0.04 0.07 −19.88 0.52 0.0810.55 0.23 0.33 0.20 0.23 SEQID-01381 0.03 0.03 0.03 0.05 0.08 0.00 0.020.09 −21.31 0.33 0.08 11.20 0.27 0.33 0.18 0.26 SEQID-01382 0.02 0.060.03 0.06 0.04 0.04 0.03 0.08 −22.43 0.32 0.02 9.05 0.23 0.30 0.00 0.00SEQID-01383 0.03 0.04 0.03 0.04 0.04 0.00 0.07 0.09 −21.66 0.27 0.1311.00 0.20 0.30 0.00 0.24 SEQID-01384 0.01 0.09 0.07 0.05 0.01 0.01 0.040.01 −12.40 0.17 0.01 7.89 0.32 0.46 0.25 0.33 SEQID-01385 0.01 0.050.04 0.05 0.03 0.00 0.04 0.05 −27.28 0.27 0.08 10.72 0.23 0.33 0.00 0.00SEQID-01386 0.04 0.05 0.05 0.07 0.05 0.02 0.03 0.07 −18.11 0.53 0.018.21 0.23 0.31 0.20 0.22 SEQID-01387 0.01 0.09 0.03 0.04 0.07 0.01 0.050.07 −21.39 0.38 −0.02 5.14 0.62 0.74 0.22 0.00 SEQID-01388 0.00 0.030.04 0.06 0.06 0.01 0.02 0.05 −27.26 0.10 0.04 10.39 0.21 0.33 0.00 0.21SEQID-01389 0.02 0.10 0.05 0.06 0.04 0.02 0.04 0.05 −20.63 0.41 0.029.11 0.22 0.31 0.00 0.00 SEQID-01390 0.03 0.05 0.03 0.06 0.05 0.00 0.060.06 −23.89 0.37 −0.01 6.33 0.23 0.32 0.00 0.00 SEQID-01391 0.02 0.070.04 0.03 0.05 0.02 0.04 0.08 −16.70 0.53 0.01 8.14 0.22 0.33 0.00 0.21SEQID-01392 0.02 0.04 0.03 0.06 0.04 0.01 0.03 0.09 −17.38 0.54 0.007.46 0.22 0.34 0.20 0.21 SEQID-01393 0.02 0.05 0.03 0.06 0.06 0.01 0.080.06 −20.13 0.33 0.01 8.32 0.20 0.33 0.22 0.22 SEQID-01394 0.03 0.060.04 0.06 0.04 0.03 0.04 0.05 −20.20 0.39 −0.01 6.61 0.20 0.33 0.00 0.20SEQID-01395 0.01 0.05 0.05 0.06 0.06 0.03 0.06 0.07 −19.55 0.44 −0.016.60 0.19 0.34 0.20 0.21 SEQID-01396 0.03 0.04 0.04 0.04 0.04 0.01 0.030.07 −23.63 0.38 −0.05 4.56 0.20 0.33 0.00 0.21 SEQID-01397 0.03 0.020.02 0.08 0.06 0.01 0.03 0.04 −26.82 0.19 −0.01 6.26 0.19 0.35 0.00 0.20SEQID-01398 0.02 0.05 0.05 0.09 0.05 0.02 0.04 0.05 −18.87 0.35 −0.016.61 0.18 0.35 0.19 0.20 SEQID-01399 0.03 0.05 0.04 0.06 0.05 0.01 0.050.08 −19.41 0.45 −0.02 5.60 0.19 0.36 0.18 0.19 SEQID-01400 0.03 0.060.02 0.08 0.04 0.00 0.02 0.03 −29.69 0.09 0.07 10.79 0.27 0.28 0.00 0.31SEQID-01401 0.03 0.08 0.04 0.03 0.03 0.08 0.05 0.04 −23.31 0.20 −0.045.02 0.26 0.26 0.00 0.25 SEQID-01402 0.01 0.06 0.02 0.06 0.07 0.00 0.050.07 −22.73 0.35 −0.03 4.74 0.26 0.33 0.25 0.27 SEQID-01403 0.01 0.020.03 0.07 0.02 0.00 0.03 0.08 −26.26 0.33 0.14 11.18 0.25 0.31 0.24 0.00SEQID-01404 0.02 0.02 0.02 0.06 0.05 0.00 0.05 0.06 −26.18 0.28 0.1311.15 0.24 0.31 0.26 0.00 SEQID-01405 0.02 0.03 0.06 0.05 0.07 0.02 0.050.06 −20.21 0.26 0.00 6.92 0.22 0.32 0.00 0.00 SEQID-01406 0.01 0.080.04 0.04 0.04 0.00 0.08 0.06 −26.17 0.22 −0.01 5.86 0.25 0.31 0.19 0.25SEQID-01407 0.04 0.03 0.03 0.05 0.05 0.00 0.06 0.03 −21.91 0.09 0.037.88 0.25 0.31 0.28 0.26 SEQID-01408 0.01 0.07 0.02 0.07 0.04 0.01 0.010.04 −29.09 0.17 0.22 11.90 0.17 0.33 0.21 0.26 SEQID-01409 0.02 0.050.04 0.07 0.06 0.04 0.05 0.10 −17.79 0.45 −0.03 4.78 0.37 0.44 0.00 0.20SEQID-01410 0.01 0.04 0.02 0.06 0.05 0.02 0.05 0.06 −21.71 0.18 0.1311.53 0.20 0.32 0.00 0.23 SEQID-01411 0.01 0.06 0.04 0.04 0.06 0.00 0.020.08 −21.92 0.43 0.17 12.23 0.21 0.31 0.00 0.25 SEQID-01412 0.02 0.050.02 0.03 0.06 0.00 0.05 0.12 −22.05 0.33 0.06 10.34 0.23 0.30 0.00 0.22SEQID-01413 0.01 0.06 0.03 0.03 0.06 0.04 0.05 0.05 −17.44 0.33 0.018.87 0.48 0.35 0.00 0.20 SEQID-01414 0.01 0.05 0.03 0.03 0.04 0.00 0.030.07 −27.84 0.28 0.12 11.14 0.20 0.31 0.21 0.00 SEQID-01415 0.02 0.020.03 0.11 0.04 0.00 0.04 0.03 −28.18 0.14 −0.06 4.54 0.23 0.33 0.00 0.22SEQID-01416 0.01 0.06 0.04 0.04 0.04 0.03 0.05 0.05 −20.77 0.35 0.007.09 0.21 0.31 0.00 0.18 SEQID-01417 0.03 0.05 0.03 0.07 0.06 0.00 0.040.05 −23.05 0.23 −0.04 4.62 0.23 0.33 0.00 0.00 SEQID-01418 0.03 0.040.03 0.04 0.08 0.01 0.03 0.06 −19.66 0.40 0.02 9.54 0.00 0.33 0.00 0.22SEQID-01419 0.02 0.04 0.05 0.04 0.06 0.01 0.04 0.10 −19.31 0.49 −0.016.27 0.22 0.32 0.00 0.20 SEQID-01420 0.01 0.05 0.05 0.07 0.08 0.00 0.040.07 −16.80 0.45 0.02 9.01 0.00 0.31 0.00 0.21 SEQID-01421 0.03 0.050.04 0.05 0.04 0.02 0.02 0.09 −19.36 0.50 −0.01 6.55 0.21 0.33 0.00 0.21SEQID-01422 0.02 0.05 0.04 0.07 0.07 0.00 0.05 0.05 −20.93 0.40 0.039.71 0.22 0.33 0.00 0.19 SEQID-01423 0.01 0.08 0.04 0.05 0.06 0.02 0.080.04 −17.98 0.41 −0.05 4.45 0.37 0.54 0.00 0.23 SEQID-01424 0.02 0.070.05 0.04 0.03 0.04 0.06 0.06 −22.06 0.41 0.01 8.13 0.21 0.35 0.00 0.21SEQID-01425 0.02 0.05 0.03 0.06 0.06 0.01 0.05 0.05 −20.51 0.40 −0.016.21 0.21 0.33 0.00 0.21 SEQID-01426 0.05 0.05 0.03 0.06 0.06 0.00 0.040.06 −17.68 0.46 0.00 7.46 0.21 0.34 0.21 0.21 SEQID-01427 0.03 0.060.06 0.04 0.05 0.02 0.04 0.06 −20.62 0.32 0.00 6.77 0.20 0.32 0.20 0.22SEQID-01428 0.02 0.07 0.04 0.04 0.04 0.01 0.08 0.05 −20.04 0.36 −0.044.95 0.21 0.34 0.00 0.21 SEQID-01429 0.02 0.05 0.02 0.09 0.05 0.07 0.060.05 −24.14 0.19 0.00 7.83 0.20 0.34 0.00 0.21 SEQID-01430 0.03 0.030.04 0.05 0.05 0.01 0.06 0.03 −25.39 0.21 −0.02 5.26 0.20 0.34 0.00 0.21SEQID-01431 0.03 0.04 0.03 0.05 0.07 0.02 0.05 0.06 −19.82 0.35 0.017.53 0.21 0.35 0.00 0.21 SEQID-01432 0.03 0.05 0.05 0.05 0.06 0.01 0.030.09 −17.16 0.51 −0.03 4.89 0.19 0.31 0.00 0.20 SEQID-01433 0.02 0.090.01 0.05 0.02 0.03 0.05 0.0J −24.24 0.10 0.16 10.56 0.28 0.20 0.34 0.32SEQID-01434 0.01 0.03 0.01 0.05 0.05 0.00 0.06 0.07 −23.87 0.28 0.1811.91 0.28 0.32 0.00 0.27 SEQID-01435 0.05 0.07 0.03 0.07 0.04 0.02 0.060.11 −18.32 0.50 −0.03 4.54 0.42 0.50 0.00 0.21 SEQID-01436 0.01 0.060.08 0.05 0.06 0.02 0.04 0.09 −16.92 0.35 −0.01 5.83 0.26 0.32 0.22 0.33SEQID-01437 0.04 0.04 0.04 0.09 0.02 0.01 0.05 0.06 −25.69 0.12 0.006.81 0.25 0.29 0.00 0.20 SEQID-01438 0.02 0.02 0.03 0.12 0.08 0.00 0.060.05 −22.27 0.21 0.11 10.74 0.24 0.29 0.00 0.25 SEQID-01439 0.02 0.010.03 0.04 0.07 0.01 0.02 0.10 −23.95 0.29 0.05 10.21 0.25 0.29 0.22 0.00SEQID-01440 0.02 0.04 0.03 0.05 0.05 0.01 0.03 0.06 −23.29 0.31 0.1911.79 0.21 0.31 0.00 0.00 SEQID-01441 0.03 0.08 0.01 0.06 0.07 0.01 0.060.05 −22.02 0.27 0.01 8.81 0.24 0.29 0.00 0.23 SEQID-01442 0.02 0.030.03 0.04 0.05 0.05 0.01 0.10 −20.71 0.50 0.14 11.62 0.23 0.32 0.24 0.23SEQID-01443 0.02 0.07 0.02 0.09 0.05 0.01 0.07 0.07 −22.98 0.32 −0.034.81 0.23 0.30 0.24 0.00 SEQID-01444 0.07 0.06 0.05 0.04 0.05 0.00 0.040.07 −20.84 0.29 0.11 11.34 0.00 0.28 0.00 0.20 SEQID-01445 0.01 0.030.06 0.05 0.03 0.00 0.02 0.07 −22.28 0.39 0.04 10.10 0.22 0.34 0.24 0.25SEQID-01446 0.02 0.01 0.00 0.07 0.02 0.02 0.03 0.01 −36.22 0.05 −0.124.18 0.32 0.38 0.22 0.27 SEQID-01447 0.03 0.05 0.02 0.04 0.06 0.01 0.040.08 −24.87 0.26 0.07 10.55 0.22 0.31 0.00 0.24 SEQID-01448 0.02 0.080.03 0.07 0.06 0.03 0.09 0.06 −14.24 0.78 0.02 9.38 0.22 0.30 0.00 0.00SEQID-01449 0.01 0.06 0.06 0.05 0.08 0.03 0.05 0.06 −17.40 0.41 0.006.97 0.20 0.35 0.00 0.20 SEQID-01450 0.03 0.03 0.03 0.07 0.02 0.03 0.020.07 −30.33 0.30 −0.12 4.11 0.00 0.31 0.00 0.22 SEQID-01451 0.01 0.060.03 0.05 0.04 0.01 0.06 0.08 −22.94 0.32 0.15 11.21 0.00 0.32 0.00 0.00SEQID-01452 0.02 0.07 0.03 0.06 0.04 0.02 0.02 0.05 −25.66 0.28 −0.114.05 0.54 0.78 0.22 0.23 SEQID-01453 0.03 0.03 0.04 0.04 0.08 0.04 0.070.08 −23.36 0.37 −0.02 6.23 0.23 0.31 0.20 0.00 SEQID-01454 0.02 0.070.05 0.02 0.05 0.02 0.06 0.07 −20.72 0.37 −0.01 6.52 0.21 0.30 0.00 0.00SEQID-01455 0.00 0.07 0.02 0.05 0.03 0.01 0.01 0.02 −33.66 0.11 −0.134.08 0.23 0.32 0.00 0.21 SEQID-01456 0.03 0.04 0.02 0.03 0.04 0.01 0.040.08 −20.05 0.44 0.02 9.68 0.21 0.33 0.00 0.00 SEQID-01457 0.01 0.070.05 0.03 0.04 0.03 0.05 0.06 −22.23 0.41 −0.01 6.05 0.22 0.33 0.20 0.00SEQID-01458 0.01 0.05 0.04 0.05 0.08 0.03 0.06 0.06 −23.62 0.34 −0.015.74 0.21 0.34 0.00 0.21 SEQID-01459 0.02 0.07 0.04 0.05 0.05 0.01 0.040.08 −17.88 0.50 −0.03 4.77 0.21 0.32 0.00 0.21 SEQID-01460 0.03 0.030.04 0.05 0.08 0.01 0.03 0.06 −18.90 0.42 0.00 6.94 0.00 0.33 0.00 0.21SEQID-01461 0.01 0.04 0.05 0.05 0.04 0.01 0.03 0.07 −19.76 0.57 0.006.71 0.22 0.34 0.00 0.21 SEQID-01462 0.02 0.06 0.03 0.04 0.07 0.01 0.030.08 −19.62 0.49 0.00 6.76 0.29 0.40 0.22 0.23 SEQID-01463 0.04 0.050.04 0.04 0.04 0.03 0.08 0.04 −21.36 0.25 −0.01 6.29 0.20 0.30 0.00 0.20SEQID-01464 0.02 0.05 0.03 0.04 0.05 0.00 0.03 0.08 −20.94 0.43 0.018.22 0.22 0.38 0.00 0.21 SEQID-01465 0.03 0.06 0.03 0.05 0.05 0.02 0.030.06 −21.35 0.43 −0.01 6.39 0.21 0.31 0.00 0.21 SEQID-01466 0.02 0.080.04 0.05 0.06 0.02 0.05 0.07 −19.43 0.41 −0.01 5.42 0.50 0.70 0.18 0.21SEQID-01467 0.01 0.04 0.03 0.06 0.05 0.01 0.05 0.06 −22.02 0.39 0.006.65 0.21 0.35 0.00 0.22 SEQID-01468 0.01 0.04 0.10 0.07 0.03 0.02 0.030.06 −27.18 0.16 −0.08 4.31 0.21 0.36 0.19 0.23 SEQID-01469 0.02 0.080.04 0.06 0.04 0.05 0.07 0.03 −23.56 0.24 −0.03 5.13 0.21 0.36 0.00 0.20SEQID-01470 0.01 0.06 0.03 0.07 0.05 0.01 0.03 0.05 −23.15 0.32 −0.026.36 0.42 0.89 0.20 0.21 SEQID-01471 0.02 0.04 0.05 0.05 0.06 0.03 0.070.08 −19.05 0.43 −0.01 6.67 0.20 0.32 0.00 0.21 SEQID-01472 0.02 0.060.05 0.05 0.06 0.02 0.03 0.06 −21.68 0.36 −0.02 5.69 0.20 0.34 0.00 0.21SEQID-01473 0.02 0.03 0.03 0.04 0.05 0.00 0.03 0.06 −25.57 0.35 0.018.24 0.20 0.34 0.43 0.22 SEQID-01474 0.02 0.02 0.03 0.09 0.10 0.03 0.100.03 −14.48 0.26 0.06 10.19 0.30 0.23 0.00 0.34 SEQID-01475 0.02 0.050.02 0.02 0.06 0.00 0.02 0.10 −27.25 0.28 −0.01 6.80 0.32 0.30 0.00 1.00SEQID-01476 0.03 0.01 0.00 0.05 0.09 0.02 0.06 0.08 −21.28 0.30 0.1911.06 0.26 0.29 0.23 0.23 SEQID-01477 0.02 0.03 0.02 0.08 0.08 0.00 0.090.08 −17.20 0.58 0.08 10.35 0.25 0.30 0.00 0.23 SEQID-01478 0.02 0.020.03 0.02 0.04 0.00 0.05 0.06 −21.71 0.38 −0.05 4.72 0.22 0.30 0.00 0.25SEQID-01479 0.02 0.00 0.03 0.07 0.03 0.02 0.05 0.05 −24.75 0.38 0.1511.02 0.22 0.26 0.00 0.24 SEQID-01480 0.04 0.05 0.04 0.06 0.04 0.00 0.040.10 −16.44 0.61 −0.03 5.10 0.24 0.36 0.20 0.00 SEQID-01481 0.03 0.050.03 0.09 0.04 0.00 0.04 0.08 −22.13 0.30 −0.04 4.57 0.24 0.29 0.24 0.25SEQID-01482 0.02 0.03 0.05 0.04 0.03 0.01 0.07 0.03 −22.78 0.33 −0.025.70 0.24 0.32 0.00 0.00 SEQID-01483 0.02 0.03 0.03 0.05 0.01 0.01 0.060.07 −22.48 0.28 0.04 10.12 0.23 0.31 0.27 0.24 SEQID-01484 0.02 0.020.04 0.03 0.06 0.00 0.08 0.09 −22.18 0.26 0.13 10.75 0.00 0.31 0.22 0.00SEQID-01485 0.03 0.02 0.02 0.06 0.04 0.00 0.04 0.05 −27.22 0.22 −0.084.33 0.21 0.31 0.22 0.27 SEQID-01486 0.02 0.02 0.04 0.07 0.03 0.02 0.070.06 −20.48 0.39 0.11 11.04 0.24 0.29 0.26 0.00 SEQID-01487 0.03 0.020.04 0.06 0.08 0.03 0.05 0.08 −19.96 0.23 −0.06 4.38 0.00 0.30 0.00 0.24SEQID-01488 0.01 0.05 0.08 0.02 0.05 0.00 0.06 0.07 −19.31 0.54 −0.084.08 0.00 0.33 0.22 0.24 SEQID-01489 0.01 0.08 0.03 0.02 0.06 0.01 0.040.07 −29.68 0.20 −0.04 6.14 0.00 0.31 0.00 0.18 SEQID-01490 0.03 0.060.04 0.06 0.05 0.00 0.01 0.05 −20.53 0.46 −0.06 4.45 0.21 0.32 0.21 0.21SEQID-01491 0.02 0.11 0.05 0.06 0.07 0.04 0.07 0.05 −12.60 0.73 0.049.74 0.00 0.31 0.00 0.22 SEQID-01492 0.01 0.06 0.04 0.05 0.05 0.02 0.070.05 −20.65 0.33 −0.01 6.07 0.19 0.30 0.00 0.00 SEQID-01493 0.02 0.080.04 0.05 0.05 0.02 0.06 0.04 −22.18 0.31 0.00 6.84 0.32 0.43 0.00 0.00SEQID-01494 0.02 0.04 0.06 0.06 0.04 0.02 0.02 0.07 −19.30 0.51 −0.025.48 0.00 0.33 0.00 0.20 SEQID-01495 0.05 0.10 0.03 0.05 0.04 0.02 0.070.03 −23.42 0.33 −0.03 4.86 0.19 0.32 0.00 0.21 SEQID-01496 0.02 0.040.04 0.05 0.06 0.00 0.04 0.07 −19.57 0.43 0.01 8.18 0.19 0.33 0.00 0.20SEQID-01497 0.02 0.06 0.02 0.04 0.04 0.02 0.08 0.05 −23.62 0.41 −0.025.11 0.22 0.33 0.00 0.19 SEQID-01498 0.02 0.05 0.04 0.04 0.04 0.03 0.070.06 −22.22 0.37 −0.01 6.62 0.21 0.31 0.00 0.22 SEQID-01499 0.01 0.030.08 0.05 0.04 0.00 0.09 0.04 −24.80 0.18 −0.05 4.73 0.21 0.36 0.00 0.22SEQID-01500 0.02 0.05 0.04 0.04 0.04 0.01 0.04 0.06 −23.45 0.41 0.007.50 0.21 0.36 0.00 0.23 SEQID-01501 0.02 0.05 0.06 0.03 0.07 0.03 0.060.05 −17.92 0.36 0.02 9.27 0.22 0.34 0.00 0.20 SEQID-01502 0.03 0.100.03 0.05 0.03 0.02 0.04 0.04 −24.51 0.40 −0.04 4.90 0.21 0.33 0.00 0.00SEQID-01503 0.02 0.05 0.05 0.05 0.04 0.02 0.04 0.06 −17.28 0.56 0.006.95 0.21 0.31 0.00 0.21 SEQID-01504 0.03 0.08 0.06 0.05 0.03 0.01 0.040.04 −22.29 0.34 −0.02 5.83 0.21 0.31 0.00 0.22 SEQID-01505 0.03 0.040.03 0.07 0.06 0.01 0.04 0.07 −16.42 0.49 −0.02 5.28 0.21 0.33 0.20 0.22SEQID-01506 0.02 0.04 0.05 0.04 0.05 0.01 0.02 0.07 −21.58 0.44 0.006.78 0.21 0.33 0.20 0.21 SEQID-01507 0.01 0.06 0.05 0.05 0.04 0.02 0.050.06 −20.35 0.44 −0.02 5.62 0.20 0.34 0.00 0.21 SEQID-01508 0.02 0.050.04 0.07 0.04 0.02 0.05 0.07 −20.70 0.35 −0.01 5.85 0.21 0.31 0.00 0.21SEQID-01509 0.03 0.05 0.04 0.03 0.05 0.03 0.05 0.06 −24.81 0.31 0.007.62 0.21 0.33 0.00 0.20 SEQID-01510 0.03 0.07 0.03 0.05 0.04 0.03 0.050.05 −23.93 0.29 0.00 7.03 0.20 0.35 0.00 0.20 SEQID-01511 0.02 0.050.04 0.06 0.04 0.01 0.04 0.08 −20.83 0.44 −0.03 4.94 0.20 0.32 0.00 0.21SEQID-01512 0.02 0.03 0.03 0.05 0.04 0.01 0.03 0.06 −27.97 0.35 −0.025.45 0.20 0.37 0.19 0.19 SEQID-01513 0.02 0.08 0.04 0.06 0.05 0.01 0.040.07 −21.63 0.39 −0.04 4.72 0.20 0.34 0.20 0.20 SEQID-01514 0.03 0.050.04 0.05 0.05 0.02 0.04 0.06 −20.91 0.39 −0.01 6.21 0.17 0.33 0.18 0.19SEQID-01515 0.05 0.07 0.08 0.06 0.08 0.04 0.06 0.01 −15.18 0.44 0.029.00 0.26 0.25 0.00 0.26 SEQID-01516 0.16 0.02 0.00 0.06 0.02 0.02 0.020.00 −26.95 0.02 0.02 9.05 0.25 0.24 0.25 0.26 SEQID-01517 0.01 0.030.04 0.03 0.01 0.00 0.05 0.02 −27.30 0.13 0.09 10.47 0.30 0.32 0.00 0.27SEQID-01518 0.04 0.05 0.05 0.03 0.05 0.00 0.03 0.02 −30.06 0.12 0.0610.32 0.22 0.31 0.25 0.25 SEQID-01519 0.04 0.03 0.03 0.06 0.05 0.00 0.030.05 −24.45 0.32 0.20 12.14 0.25 0.27 0.00 0.25 SEQID-01520 0.01 0.050.05 0.06 0.05 0.00 0.08 0.08 −18.79 0.42 0.03 9.40 0.23 0.28 0.00 0.29SEQID-01521 0.02 0.04 0.04 0.04 0.04 0.00 0.01 0.11 −19.76 0.50 0.029.69 0.27 0.31 0.00 0.26 SEQID-01522 0.02 0.05 0.03 0.06 0.04 0.02 0.080.09 −18.64 0.27 0.16 11.63 0.24 0.30 0.00 0.21 SEQID-01523 0.02 0.010.06 0.05 0.01 0.00 0.05 0.07 −25.54 0.24 0.20 11.52 0.18 0.30 0.21 0.22SEQID-01524 0.01 0.02 0.01 0.04 0.05 0.00 0.00 0.05 −31.23 0.13 −0.025.11 0.29 0.33 0.27 0.22 SEQID-01525 0.01 0.01 0.03 0.05 0.04 0.00 0.030.04 −18.10 0.37 0.10 11.34 0.26 0.30 0.28 0.25 SEQID-01526 0.05 0.030.05 0.06 0.02 0.03 0.02 0.10 −17.41 0.58 0.09 11.03 0.25 0.29 0.27 0.00SEQID-01527 0.02 0.02 0.03 0.04 0.05 0.03 0.07 0.08 −16.35 0.41 −0.025.59 0.37 0.37 0.23 0.19 SEQID-01528 0.03 0.04 0.06 0.10 0.01 0.04 0.060.07 −19.64 0.29 −0.01 6.35 0.21 0.30 0.22 0.00 SEQID-01529 0.03 0.060.05 0.07 0.04 0.00 0.04 0.11 −15.90 0.43 0.03 9.76 0.23 0.30 0.24 0.00SEQID-01530 0.03 0.03 0.03 0.04 0.03 0.00 0.02 0.07 −22.46 0.32 −0.044.57 0.38 0.44 0.21 0.21 SEQID-01531 0.04 0.06 0.01 0.05 0.06 0.05 0.040.06 −19.58 0.45 0.00 7.51 0.00 0.32 0.00 0.22 SEQID-01532 0.01 0.110.05 0.03 0.02 0.00 0.05 0.05 −18.49 0.58 −0.03 4.75 0.00 0.31 0.00 0.26SEQID-01533 0.03 0.05 0.03 0.06 0.04 0.00 0.08 0.07 −22.34 0.40 −0.016.13 0.24 0.31 0.00 0.22 SEQID-01534 0.01 0.06 0.05 0.06 0.06 0.06 0.010.06 −24.06 0.27 −0.03 5.17 0.24 0.31 0.00 0.22 SEQID-01535 0.02 0.050.02 0.06 0.04 0.01 0.05 0.09 −20.98 0.45 −0.01 5.45 0.22 0.34 0.24 0.00SEQID-01536 0.03 0.05 0.04 0.04 0.05 0.01 0.03 0.06 −23.96 0.38 −0.016.30 0.22 0.33 0.00 0.21 SEQID-01537 0.01 0.03 0.03 0.07 0.08 0.00 0.040.09 −16.54 0.54 −0.06 4.27 0.23 0.31 0.21 0.00 SEQID-01538 0.03 0.080.05 0.07 0.01 0.02 0.07 0.04 −21.18 0.36 −0.01 6.64 0.23 0.34 0.00 0.00SEQID-01539 0.05 0.02 0.02 0.07 0.04 0.01 0.00 0.04 −27.29 0.18 −0.084.37 0.24 0.35 0.00 0.00 SEQID-01540 0.02 0.07 0.02 0.03 0.03 0.02 0.030.05 −28.85 0.29 −0.09 4.76 0.23 0.30 0.00 0.22 SEQID-01541 0.04 0.060.04 0.04 0.06 0.03 0.08 0.07 −15.44 0.75 −0.06 4.20 0.21 0.32 0.00 0.20SEQID-01542 0.03 0.09 0.03 0.07 0.04 0.00 0.02 0.04 −22.95 0.51 −0.084.18 0.23 0.32 0.00 0.22 SEQID-01543 0.03 0.04 0.02 0.07 0.05 0.01 0.050.05 −23.39 0.40 −0.08 4.38 0.00 0.33 0.22 0.00 SEQID-01544 0.04 0.030.04 0.05 0.06 0.02 0.06 0.03 −18.90 0.44 0.05 8.97 0.22 0.31 0.00 0.20SEQID-01545 0.02 0.06 0.02 0.06 0.05 0.04 0.06 0.06 −18.02 0.41 −0.016.16 0.20 0.32 0.00 0.00 SEQID-01546 0.00 0.02 0.03 0.07 0.06 0.08 0.090.08 −20.14 0.42 −0.03 5.54 0.21 0.32 0.00 0.20 SEQID-01547 0.02 0.050.06 0.06 0.06 0.03 0.07 0.05 −18.75 0.39 0.01 8.29 0.21 0.35 0.20 0.22SEQID-01548 0.03 0.07 0.05 0.05 0.03 0.02 0.08 0.04 −22.52 0.29 −0.025.16 0.21 0.32 0.00 0.25 SEQID-01549 0.03 0.02 0.02 0.08 0.07 0.00 0.060.07 −19.16 0.29 0.00 7.40 0.22 0.31 0.22 0.18 SEQID-01550 0.01 0.030.05 0.04 0.05 0.04 0.04 0.07 −20.54 0.32 0.01 8.22 0.23 0.31 0.00 0.20SEQID-01551 0.03 0.06 0.05 0.05 0.07 0.00 0.03 0.06 −17.15 0.48 0.018.76 0.21 0.31 0.00 0.20 SEQID-01552 0.02 0.04 0.04 0.04 0.04 0.01 0.040.06 −23.14 0.35 −0.06 4.51 0.22 0.31 0.00 0.00 SEQID-01553 0.02 0.080.03 0.06 0.04 0.01 0.03 0.07 −22.22 0.40 −0.01 6.06 0.22 0.32 0.00 0.00SEQID-01554 0.02 0.05 0.05 0.04 0.05 0.02 0.06 0.05 −21.32 0.33 −0.025.83 0.23 0.32 0.00 0.22 SEQID-01555 0.02 0.05 0.05 0.04 0.05 0.01 0.020.08 −21.34 0.43 −0.01 6.30 0.21 0.32 0.23 0.22 SEQID-01556 0.03 0.060.02 0.05 0.06 0.02 0.09 0.03 −20.12 0.32 −0.07 4.22 0.19 0.35 0.00 0.18SEQID-01557 0.01 0.07 0.03 0.05 0.04 0.03 0.05 0.08 −18.69 0.55 0.018.39 0.20 0.35 0.00 0.20 SEQID-01558 0.03 0.04 0.04 0.04 0.04 0.03 0.080.04 −21.38 0.36 −0.01 6.19 0.20 0.32 0.00 0.20 SEQID-01559 0.03 0.040.06 0.06 0.07 0.00 0.02 0.06 −20.66 0.33 −0.10 3.97 0.21 0.35 0.00 0.22SEQID-01560 0.02 0.07 0.05 0.08 0.06 0.01 0.04 0.05 −15.08 0.37 −0.015.18 0.22 0.33 0.21 0.21 SEQID-01561 0.03 0.07 0.03 0.03 0.07 0.03 0.040.05 −19.53 0.40 −0.02 5.49 0.20 0.33 0.00 0.20 SEQID-01562 0.01 0.050.03 0.17 0.03 0.01 0.02 0.03 −28.73 0.13 −0.05 4.58 0.26 0.57 0.21 0.22SEQID-01563 0.02 0.03 0.04 0.09 0.04 0.00 0.02 0.04 −29.57 0.18 −0.114.19 0.22 0.32 0.23 0.22 SEQID-01564 0.02 0.06 0.04 0.05 0.06 0.02 0.050.06 −17.13 0.41 0.01 8.55 0.22 0.35 0.00 0.20 SEQID-01565 0.01 0.030.06 0.07 0.05 0.02 0.01 0.04 −30.23 0.14 −0.08 4.43 0.21 0.34 0.00 0.22SEQID-01566 0.03 0.05 0.04 0.03 0.05 0.00 0.03 0.04 −25.47 0.32 −0.025.45 0.22 0.32 0.20 0.22 SEQID-01567 0.03 0.04 0.05 0.07 0.08 0.00 0.030.07 −21.91 0.33 0.01 9.44 0.21 0.34 0.22 0.21 SEQID-01568 0.04 0.070.03 0.06 0.05 0.02 0.04 0.06 −19.23 0.32 −0.06 4.37 0.40 0.54 0.00 0.21SEQID-01569 0.03 0.06 0.02 0.05 0.06 0.02 0.05 0.04 −21.49 0.37 −0.025.48 0.22 0.32 0.00 0.22 SEQID-01570 0.01 0.06 0.03 0.05 0.02 0.02 0.060.05 −25.30 0.30 −0.01 5.94 0.21 0.34 0.19 0.21 SEQID-01571 0.01 0.060.05 0.05 0.03 0.02 0.07 0.04 −21.09 0.35 0.00 6.79 0.21 0.37 0.00 0.21SEQID-01572 0.03 0.06 0.04 0.06 0.05 0.01 0.02 0.06 −17.35 0.38 0.028.40 0.21 0.31 0.00 0.21 SEQID-01573 0.02 0.08 0.03 0.06 0.05 0.01 0.050.05 −20.75 0.36 −0.01 5.30 0.22 0.14 0.00 0.21 SEQID-01574 0.01 0.070.04 0.05 0.05 0.02 0.04 0.06 −20.80 0.41 −0.02 5.63 0.20 0.33 0.00 0.21SEQID-01575 0.03 0.05 0.04 0.04 0.06 0.02 0.04 0.07 −20.18 0.41 −0.016.47 0.21 0.33 0.00 0.21 SEQID-01576 0.03 0.05 0.05 0.03 0.08 0.02 0.050.06 −19.53 0.33 0.00 7.20 0.20 0.32 0.00 0.21 SEQID-01577 0.03 0.040.04 0.05 0.08 0.02 0.04 0.06 −21.89 0.35 0.00 6.82 0.21 0.32 0.20 0.21SEQID-01578 0.04 0.09 0.03 0.06 0.08 0.03 0.07 0.07 −14.76 0.73 0.007.66 0.20 0.33 0.00 0.22 SEQID-01579 0.03 0.06 0.04 0.05 0.05 0.01 0.040.06 −22.28 0.41 −0.02 5.55 0.21 0.34 0.00 0.21 SEQID-01580 0.02 0.050.04 0.05 0.06 0.01 0.04 0.07 −24.31 0.31 −0.02 5.29 0.46 0.61 0.00 0.21SEQID-01581 0.03 0.08 0.04 0.05 0.04 0.03 0.08 0.05 −20.71 0.35 −0.026.10 0.21 0.31 0.00 0.21 SEQID-01582 0.01 0.02 0.03 0.07 0.08 0.01 0.030.04 −28.38 0.10 −0.05 4.68 0.21 0.40 0.00 0.20 SEQID-01583 0.02 0.060.04 0.05 0.05 0.02 0.06 0.07 −24.33 0.25 0.01 8.67 0.20 0.33 0.00 0.20SEQID-01584 0.02 0.05 0.05 0.04 0.06 0.00 0.03 0.07 −18.52 0.45 0.006.83 0.19 0.34 0.00 0.20 SEQID-01585 0.01 0.07 0.03 0.04 0.05 0.01 0.050.05 −23.50 0.29 −0.02 5.39 0.20 0.35 0.19 0.20 SEQID-01586 0.01 0.060.04 0.06 0.05 0.03 0.05 0.05 −20.61 0.30 0.00 7.23 0.19 0.33 0.20 0.20SEQID-01587 0.02 0.07 0.04 0.06 0.05 0.04 0.06 0.05 −21.13 0.26 0.007.26 0.19 0.32 0.19 0.20 SEQID-01588 0.04 0.04 0.03 0.04 0.07 0.00 0.020.08 −21.16 0.46 −0.02 5.25 0.21 0.32 0.21 0.21 SEQID-01589 0.03 0.040.04 0.04 0.05 0.01 0.04 0.07 −22.97 0.34 0.00 7.14 0.19 0.35 0.19 0.19SEQID-01590 0.02 0.01 0.04 0.05 0.05 0.01 0.04 0.05 −22.07 0.27 0.1111.06 0.21 0.34 0.17 0.23 SEQID-01591 0.04 0.04 0.03 0.05 0.09 0.01 0.050.07 −18.50 0.40 −0.01 6.10 0.42 0.59 0.00 0.20 SEQID-01592 0.04 0.040.03 0.04 0.05 0.00 0.05 0.06 −22.72 0.32 −0.06 4.52 0.49 0.68 0.00 0.20SEQID-01593 0.03 0.04 0.04 0.01 0.08 0.00 0.04 0.09 −22.55 0.42 −0.064.66 0.22 0.35 0.00 0.21 SEQID-01594 0.01 0.05 0.02 0.07 0.03 0.00 0.020.10 −25.27 0.36 −0.02 5.08 0.21 0.31 0.21 0.23 SEQID-01595 0.05 0.050.04 0.02 0.05 0.02 0.03 0.08 −23.32 0.48 −0.05 4.51 0.21 0.33 0.23 0.00SEQID-01596 0.06 0.05 0.01 0.04 0.03 0.01 0.06 0.04 −24.98 0.25 0.2111.84 0.00 0.27 0.00 0.22 SEQID-01597 0.04 0.04 0.05 0.04 0.05 0.01 0.040.10 −19.93 0.37 0.02 9.66 0.21 0.32 0.00 0.00 SEQID-01598 0.04 0.040.03 0.03 0.04 0.03 0.04 0.04 −25.91 0.31 −0.01 6.52 0.21 0.32 0.00 0.20SEQID-01599 0.02 0.05 0.04 0.05 0.05 0.03 0.05 0.06 −21.91 0.32 −0.016.39 0.20 0.33 0.00 0.20 SEQID-01600 0.04 0.03 0.04 0.04 0.04 0.02 0.040.08 −20.96 0.45 −0.03 5.00 0.24 0.33 0.20 0.00 SEQID-01601 0.01 0.030.04 0.05 0.07 0.00 0.06 0.10 −23.64 0.26 0.04 9.92 0.24 0.30 0.00 0.24SEQID-01602 0.04 0.05 0.02 0.03 0.05 0.00 0.05 0.07 −20.74 0.48 −0.035.74 0.21 0.32 0.22 0.22 SEQID-01603 0.03 0.03 0.04 0.04 0.04 0.00 0.020.08 −25.70 0.29 0.04 10.27 0.19 0.33 0.00 0.20 SEQID-01604 0.01 0.040.03 0.07 0.13 0.00 0.08 0.10 −16.36 0.36 0.03 9.90 0.23 0.36 0.23 0.23SEQID-01605 0.04 0.01 0.05 0.06 0.05 0.00 0.07 0.09 −21.11 0.22 0.1511.42 0.23 0.31 0.00 0.00 SEQID-01606 0.04 0.05 0.04 0.04 0.06 0.01 0.040.07 −22.99 0.36 −0.04 4.73 0.19 0.35 0.00 0.21 SEQID-01607 0.04 0.020.03 0.04 0.04 0.00 0.01 0.11 −23.44 0.40 0.07 10.98 0.00 0.30 0.00 0.24SEQID-01608 0.03 0.02 0.04 0.04 0.06 0.01 0.04 0.13 −22.45 0.33 0.0810.62 0.24 0.33 0.00 0.25 SEQID-01609 0.03 0.02 0.03 0.03 0.04 0.04 0.030.06 −23.54 0.22 0.07 10.93 0.00 0.33 0.00 0.00 SEQID-01610 0.03 0.040.04 0.04 0.06 0.01 0.04 0.07 −22.98 0.34 −0.02 5.30 0.21 0.37 0.00 0.22SEQID-01611 0.03 0.02 0.04 0.05 0.05 0.02 0.05 0.06 −23.03 0.35 −0.054.54 0.42 0.59 0.00 0.00 SEQID-01612 0.05 0.03 0.05 0.05 0.06 0.00 0.050.06 −18.79 0.54 −0.02 5.06 0.21 0.32 0.00 0.23 SEQID-01613 0.03 0.040.02 0.03 0.04 0.02 0.04 0.05 −23.26 0.34 −0.05 4.63 0.21 0.34 0.24 0.00SEQID-01614 0.02 0.05 0.03 0.07 0.083 0.04 0.07 0.06 −19.94 0.27 0.0510.11 0.21 0.33 0.00 0.21 SEQID-01615 0.03 0.08 0.04 0.04 0.06 0.01 0.040.09 −15.06 0.74 0.00 6.63 0.21 0.35 0.00 0.20 SEQID-01616 0.02 0.030.03 0.08 0.11 0.01 0.09 0.07 −15.18 0.29 0.04 9.91 0.21 0.33 0.22 0.21SEQID-01617 0.03 0.05 0.03 0.03 0.04 0.00 0.07 0.08 −29.91 0.24 −0.025.24 0.23 0.32 0.00 0.17 SEQID-01618 0.03 0.03 0.03 0.05 0.03 0.02 0.060.06 −23.87 0.26 0.05 10.31 0.00 0.30 0.00 0.23 SEQID-01619 0.03 0.050.04 0.04 0.04 0.01 0.02 0.08 −21.83 0.44 −0.02 5.34 0.23 0.35 0.24 0.21SEQID-01620 0.03 0.06 0.03 0.05 0.04 0.01 0.08 0.05 −21.00 0.36 −0.044.69 0.21 0.33 0.00 0.22 SEQID-01621 0.01 0.06 0.04 0.04 0.04 0.00 0.000.08 −24.08 0.36 0.05 10.32 0.30 0.31 0.00 0.00 SEQID-01622 0.04 0.050.03 0.04 0.04 0.01 0.07 0.06 −20.44 0.39 0.01 7.92 0.20 0.31 0.00 0.21SEQID-01623 0.01 0.03 0.03 0.01 0.06 0.00 0.04 0.11 −26.56 0.28 0.1011.20 0.23 0.33 0.00 0.00 SEQID-01624 0.03 0.05 0.04 0.06 0.06 0.03 0.090.06 −19.40 0.27 0.06 10.13 0.20 0.34 0.20 0.20 SEQID-01625 0.03 0.030.01 0.10 0.06 0.01 0.07 0.06 −20.45 0.28 0.09 10.47 0.22 0.31 0.00 0.22SEQID-01626 0.05 0.07 0.05 0.05 0.04 0.02 0.09 0.06 −16.88 0.71 −0.016.08 0.19 0.35 0.20 0.20 SEQID-01627 0.03 0.04 0.03 0.04 0.06 0.03 0.050.06 −23.61 0.26 −0.02 6.28 0.21 0.34 0.00 0.22 SEQID-01628 0.05 0.030.06 0.06 0.08 0.00 0.01 0.04 −23.11 0.37 0.04 10.15 0.25 0.27 0.00 0.00SEQID-01629 0.04 0.01 0.02 0.04 0.05 0.00 0.11 0.12 −28.97 0.26 0.1410.65 0.19 0.27 0.00 0.00 SEQID-01630 0.02 0.03 0.03 0.05 0.04 0.00 0.010.12 −23.06 0.57 0.07 10.72 0.27 0.33 0.25 0.23 SEQID-01631 0.03 0.020.03 0.05 0.03 0.01 0.06 0.08 −21.94 0.44 0.03 9.85 0.24 0.30 0.20 0.18SEQID-01632 0.02 0.00 0.02 0.03 0.05 0.00 0.05 0.08 −29.33 0.29 0.1110.97 0.24 0.33 0.29 0.24 SEQID-01633 0.05 0.02 0.02 0.02 0.06 0.00 0.090.08 −27.40 0.39 0.09 10.88 0.27 0.32 0.23 0.24 SEQID-01634 0.03 0.050.03 0.04 0.04 0.02 0.04 0.05 −19.86 0.54 −0.01 6.70 0.20 0.34 0.00 0.21SEQID-01635 0.03 0.04 0.05 0.05 0.04 0.01 0.05 0.07 −18.51 0.45 −0.034.81 0.21 0.33 0.20 0.12 SEQID-01636 0.02 0.01 0.02 0.03 0.07 0.00 0.020.08 −22.43 0.41 −0.03 4.70 0.21 0.35 0.23 0.12 SEQID-01637 0.01 0.050.01 0.04 0.01 0.00 0.01 0.07 −31.55 0.39 −0.18 3.88 0.24 0.30 0.24 0.25SEQID-01638 0.03 0.04 0.01 0.04 0.04 0.01 0.03 0.04 −28.30 0.24 −0.025.58 0.19 0.55 0.18 0.00 SEQID-01639 0.03 0.04 0.01 0.04 0.04 0.01 0.030.04 −28.28 0.23 −0.02 5.65 0.19 0.55 0.18 0.17 SEQID-01640 0.03 0.040.01 0.04 0.04 0.01 0.03 0.04 −28.28 0.23 −0.02 5.64 0.18 0.54 0.18 0.00SEQID-01641 0.03 0.04 0.01 0.04 0.04 0.01 0.03 0.04 −28.15 0.23 −0.025.68 0.18 0.55 0.18 0.00 SEQID-01642 0.03 0.02 0.03 0.05 0.04 0.02 0.080.05 −25.06 0.21 0.09 9.44 0.00 0.34 0.00 0.00 SEQID-01643 0.02 0.040.05 0.06 0.07 0.02 0.05 0.08 −22.60 0.30 −0.01 6.25 0.00 0.34 0.00 0.18SEQID-01644 0.05 0.04 0.04 0.05 0.06 0.02 0.06 0.05 −19.69 0.41 −0.035.05 0.19 0.30 0.00 0.20 SEQID-01645 0.04 0.06 0.05 0.04 0.04 0.02 0.030.05 −24.11 0.30 0.00 7.00 0.43 0.66 0.00 0.20 SEQID-01646 0.05 0.040.03 0.04 0.04 0.01 0.02 0.08 −21.25 0.45 0.01 7.66 0.21 0.35 0.00 0.21SEQID-01647 0.02 0.04 0.06 0.04 0.05 0.03 0.03 0.09 −24.19 0.30 0.006.53 0.18 0.34 0.20 0.21 SEQID-01648 0.05 0.05 0.04 0.05 0.06 0.02 0.060.05 −19.52 0.43 −0.03 5.16 0.21 0.31 0.00 0.22 SEQID-01649 0.04 0.060.03 0.05 0.04 0.02 0.01 0.10 −20.59 0.46 0.01 8.29 0.23 0.36 0.00 0.22SEQID-01650 0.03 0.05 0.03 0.04 0.04 0.01 0.03 0.07 −21.15 0.42 0.017.67 0.81 0.98 0.21 0.21 SEQID-01651 0.04 0.04 0.03 0.04 0.04 0.03 0.040.03 −24.31 0.28 −0.03 5.06 0.20 0.36 0.00 0.19 SEQID-01652 0.03 0.050.04 0.04 0.06 0.02 0.03 0.08 −18.95 0.64 −0.02 5.08 0.19 0.35 0.15 0.20SEQID-01653 0.04 0.05 0.03 0.05 0.06 0.02 0.04 0.10 −17.92 0.49 0.028.82 0.70 0.86 0.00 0.20 SEQID-01654 0.02 0.03 0.07 0.05 0.07 0.03 0.050.09 −23.26 0.28 −0.01 6.41 0.21 0.34 0.00 0.23 SEQID-01655 0.03 0.070.04 0.04 0.05 0.01 0.05 0.06 −19.82 0.43 0.02 9.13 0.20 0.36 0.19 0.21SEQID-01656 0.04 0.07 0.04 0.05 0.03 0.00 0.05 0.05 −22.74 0.38 −0.025.47 1.00 1.00 0.00 0.20 SEQID-01657 0.03 0.05 0.05 0.04 0.04 0.03 0.060.05 −19.55 0.37 0.00 6.93 0.18 0.34 0.19 0.00 SEQID-01658 0.01 0.040.03 0.04 0.04 0.03 0.02 0.08 −19.93 0.45 0.00 7.24 0.67 0.80 0.23 0.22SEQID-01659 0.01 0.04 0.05 0.05 0.07 0.02 0.04 0.07 −23.94 0.29 −0.025.25 0.19 0.37 0.19 0.19 SEQID-01660 0.03 0.06 0.04 0.03 0.04 0.02 0.060.06 −22.25 0.32 −0.01 6.28 0.19 0.32 0.00 0.21 SEQID-01661 0.01 0.050.04 0.06 0.05 0.03 0.06 0.08 −22.31 0.32 −0.01 6.28 0.19 0.34 0.19 0.20SEQID-01662 0.03 0.03 0.03 0.06 0.04 0.03 0.02 0.10 −19.92 0.55 0.028.02 0.23 0.32 0.20 0.19 SEQID-01663 0.01 0.04 0.03 0.06 0.07 0.02 0.040.07 −24.15 0.31 −0.02 5.47 0.00 0.38 0.00 0.00 SEQID-01664 0.05 0.090.04 0.03 0.05 0.01 0.02 0.05 −25.42 0.34 −0.05 4.48 0.41 0.59 0.23 0.23SEQID-01665 0.03 0.07 0.04 0.04 0.06 0.04 0.04 0.05 −19.34 0.41 0.018.10 0.21 0.32 0.00 0.20 SEQID-01666 0.03 0.03 0.03 0.04 0.06 0.00 0.060.07 −25.16 0.32 0.02 8.95 0.22 0.33 0.00 0.22 SEQID-01667 0.05 0.020.02 0.04 0.02 0.01 0.02 0.04 −32.61 0.15 0.04 9.81 0.25 0.33 0.26 0.24SEQID-01668 0.03 0.05 0.05 0.04 0.05 0.02 0.04 0.07 −22.22 0.37 0.028.84 0.38 0.60 0.00 0.22 SEQID-01669 0.03 0.05 0.03 0.04 0.07 0.00 0.040.06 −23.34 0.33 −0.01 5.34 0.71 0.89 0.00 0.21 SEQID-01670 0.02 0.030.19 0.03 0.03 0.01 0.02 0.03 −14.79 0.16 −0.01 5.27 0.61 0.78 0.21 0.39SEQID-01671 0.04 0.07 0.07 0.02 0.04 0.00 0.01 0.05 −23.56 0.32 −0.044.68 0.31 0.49 0.00 0.22 SEQID-01672 0.03 0.04 0.05 0.03 0.04 0.05 0.030.05 −22.65 0.31 0.01 7.60 0.23 0.30 0.20 0.20 SEQID-01673 0.02 0.030.11 0.04 0.06 0.02 0.03 0.06 −21.53 0.26 0.01 7.60 0.21 0.41 0.21 0.22SEQID-01674 0.02 0.05 0.04 0.06 0.05 0.03 0.05 0.08 −22.52 0.31 −0.025.83 0.19 0.33 0.19 0.19 SEQID-01675 0.02 0.05 0.03 0.04 0.04 0.01 0.040.08 −21.06 0.43 0.00 6.53 0.85 0.96 0.21 0.22 SEQID-01676 0.02 0.050.04 0.04 0.07 0.01 0.03 0.06 −22.28 0.54 −0.02 5.31 0.73 0.91 0.20 0.22SEQID-01677 0.02 0.05 0.05 0.05 0.05 0.00 0.03 0.08 −18.73 0.43 0.006.68 0.00 0.52 0.18 1.00 SEQID-01678 0.01 0.03 0.19 0.03 0.03 0.01 0.020.0

−13.57 0.17 0.01 9.57 0.84 0.96 0.22 0.39 SEQID-01679 0.00 0.02 0.020.02 0.02 0.02 0.03 0.02 −36.28 0.11 0.01 7.24 0.24 0.37 0.23 0.23SEQID-01680 0.02 0.03 0.06 0.07 0.06 0.03 0.06 0.05 −14.89 0.38 0.006.51 0.23 0.33 0.24 0.24 SEQID-01681 0.03 0.08 0.02 0.04 0.03 0.03 0.060.07 −17.57 0.56 0.06 10.24 0.20 0.31 0.22 0.00 SEQID-01682 0.03 0.080.03 0.02 0.03 0.02 0.03 0.05 −31.94 0.40 −0.19 3.81 0.21 0.33 0.00 0.23SEQID-01683 0.03 0.04 0.05 0.05 0.06 0.02 0.04 0.08 −20.68 0.41 0.039.50 0.21 0.34 0.00 0.22 SEQID-01684 0.02 0.07 0.06 0.05 0.05 0.01 0.050.04 −20.28 0.38 0.01 8.43 0.22 0.32 0.19 0.23 SEQID-01685 0.04 0.040.04 0.05 0.06 0.00 0.07 0.07 −19.87 0.53 0.01 8.17 0.22 0.34 0.00 0.21SEQID-01686 0.03 0.04 0.01 0.05 0.05 0.00 0.04 0.05 −25.43 0.18 −0.025.27 0.29 0.46 0.00 0.21 SEQID-01687 0.03 0.06 0.03 0.05 0.04 0.02 0.040.05 −21.38 0.46 −0.02 5.37 0.00 0.34 0.00 0.18 SEQID-01688 0.03 0.050.06 0.05 0.06 0.00 0.02 0.08 −16.80 0.55 0.02 8.74 0.51 0.70 0.00 0.00SEQID-01689 0.04 0.04 0.03 0.05 0.05 0.02 0.04 0.07 −18.64 0.49 0.017.89 0.19 0.34 0.00 0.21 SEQID-01690 0.02 0.04 0.05 0.10 0.07 0.01 0.040.06 −22.89 0.22 0.01 8.52 0.19 0.40 0.20 0.20 SEQID-01691 0.02 0.000.00 0.04 0.03 0.00 0.03 0.03 −36.78 0.12 −0.09 4.39 0.59 0.70 0.26 0.22SEQID-01692 0.04 0.05 0.03 0.06 0.04 0.03 0.05 0.05 −19.60 0.40 0.049.78 0.21 0.32 0.00 0.20 SEQID-01693 0.05 0.07 0.04 0.05 0.06 0.01 0.050.06 −19.49 0.31 −0.05 4.52 0.40 0.54 0.00 0.22 SEQID-01694 0.03 0.040.03 0.05 0.05 0.00 0.04 0.08 −18.98 0.46 0.02 9.56 0.21 0.34 0.00 0.22SEQID-01695 0.02 0.04 0.08 0.04 0.05 0.01 0.04 0.05 −20.77 0.34 −0.015.62 0.26 0.54 0.20 0.30 SEQID-01696 0.00 0.05 0.03 0.06 0.11 0.03 0.030.07 −23.51 0.35 −0.02 4.88 0.30 0.19 0.00 0.36 SEQID-01697 0.01 0.070.02 0.08 0.09 0.02 0.06 0.05 −17.82 0.30 0.01 8.88 0.20 0.32 0.00 0.00SEQID-01698 0.04 0.05 0.08 0.06 0.05 0.01 0.06 0.04 −20.82 0.18 0.039.60 0.18 0.33 0.00 0.23 SEQID-01699 0.02 0.04 0.04 0.06 0.07 0.01 0.050.05 −17.51 0.40 0.02 8.79 0.10 0.33 0.00 0.21 SEQID-01700 0.03 0.030.02 0.05 0.04 0.00 0.07 0.04 −25.38 0.35 0.00 7.40 0.21 0.33 0.00 0.00SEQID-01701 0.04 0.09 0.05 0.05 0.04 0.03 0.07 0.05 −16.01 0.54 0.049.63 0.19 0.30 0.00 0.21 SEQID-01702 0.02 0.06 0.04 0.04 0.06 0.01 0.060.06 −20.11 0.37 −0.05 4.74 0.95 1.00 0.20 0.22 SEQID-01703 0.04 0.060.04 0.05 0.04 0.01 0.07 0.05 −21.59 0.32 0.00 7.30 0.20 0.31 0.00 0.21SEQID-01704 0.02 0.02 0.03 0.06 0.03 0.02 0.02 0.03 −24.91 0.22 −0.035.14 0.20 0.37 0.00 0.21 SEQID-01705 0.04 0.05 0.05 0.04 0.04 0.02 0.050.08 −18.71 0.48 0.00 7.01 0.20 0.32 0.19 0.21 SEQID-01706 0.04 0.050.04 0.04 0.04 0.02 0.03 0.08 −19.28 0.44 −0.01 5.54 0.20 0.36 0.00 0.23SEQID-01707 0.03 0.04 0.06 0.04 0.05 0.02 0.04 0.08 −19.01 0.52 0.049.77 0.21 0.34 0.22 0.23 SEQID-01708 0.04 0.05 0.04 0.04 0.05 0.02 0.020.07 −19.00 0.45 −0.01 5.91 0.20 0.33 0.00 0.21 SEQID-01709 0.03 0.050.03 0.06 0.06 0.03 0.04 0.11 −19.75 0.48 0.00 7.59 0.88 0.98 0.20 0.00SEQID-01710 0.03 0.06 0.04 0.05 0.04 0.02 0.07 0.05 −20.59 0.40 −0.016.34 0.20 0.34 0.00 0.21 SEQID-01711 0.04 0.05 0.05 0.04 0.03 0.01 0.020.12 −19.29 0.53 0.00 6.72 0.27 0.34 0.00 0.21 SEQID-01712 0.05 0.050.05 0.04 0.03 0.01 0.02 0.12 −19.24 0.54 0.00 6.72 0.27 0.33 0.00 0.20SEQID-01713 0.03 0.05 0.03 0.03 0.06 0.02 0.05 0.06 −24.64 0.80 0.1310.78 0.67 0.76 0.00 0.18 SEQID-01714 0.03 0.08 0.03 0.06 0.06 0.02 0.040.08 −12.35 0.97 −0.01 5.13 0.20 0.34 0.19 0.20 SEQID-01715 0.05 0.020.04 0.04 0.02 0.02 0.03 0.04 −29.46 0.20 0.22 11.90 0.25 0.32 0.00 0.22SEQID-01716 0.04 0.02 0.03 0.05 0.03 0.02 0.03 0.04 −29.79 0.14 0.2211.90 0.26 0.31 0.18 0.20 SEQID-01717 0.03 0.08 0.03 0.06 0.06 0.02 0.050.08 −12.15 0.97 −0.01 5.37 0.20 0.34 0.20 0.21 SEQID-01718 0.01 0.030.04 0.03 0.04 0.04 0.07 0.07 −25.61 0.22 0.21 12.15 0.23 0.31 0.00 0.22SEQID-01719 0.03 0.07 0.03 0.06 0.05 0.01 0.05 0.09 −12.62 0.98 −0.025.14 0.20 0.34 0.21 0.21 SEQID-01720 0.02 0.05 0.05 0.04 0.03 0.06 0.030.08 −20.31 0.88 0.00 7.19 0.22 0.33 0.22 0.22 SEQID-01721 0.03 0.050.04 0.04 0.07 0.01 0.04 0.08 −22.00 0.41 0.04 9.79 0.22 0.35 0.21 0.22SEQID-01722 0.03 0.06 0.04 0.07 0.02 0.01 0.05 0.08 −16.23 0.49 0.006.79 0.37 0.58 0.00 0.22 SEQID-01723 0.02 0.04 0.03 0.05 0.05 0.00 0.030.05 −27.65 0.24 0.16 11.39 0.20 0.34 0.19 0.00 SEQID-01724 0.05 0.040.05 0.06 0.05 0.02 0.06 0.06 −19.93 0.44 −0.08 5.06 0.21 0.34 0.00 0.19SEQID-01725 0.05 0.04 0.04 0.05 0.06 0.02 0.06 0.05 −19.69 0.41 −0.085.05 0.20 0.31 0.00 0.21 SEQID-01726 0.04 0.02 0.04 0.05 0.03 0.02 0.030.05 −29.76 0.17 0.22 12.00 0.26 0.32 0.20 0.23 SEQID-01727 0.01 0.010.13 0.04 0.04 0.00 0.01 0.07 −23.43 0.24 0.21 11.50 0.29 0.39 0.24 0.26SEQID-01728 0.01 0.03 0.04 0.04 0.06 0.01 0.06 0.06 −20.62 0.42 0.017.71 0.22 0.33 0.22 0.21 SEQID-01729 0.05 0.04 0.05 0.05 0.06 0.02 0.060.06 −19.71 0.44 −0.03 5.16 0.20 0.33 0.00 0.21 SEQID-01730 0.04 0.050.05 0.07 0.05 0.01 0.05 0.06 −16.27 0.44 0.01 8.56 0.21 0.34 0.00 0.22SEQID-01731 0.04 0.09 0.05 0.04 0.06 0.01 0.03 0.10 −17.51 0.37 0.038.95 0.80 0.84 0.00 0.24 SEQID-01732 0.01 0.04 0.02 0.01 0.07 0.00 0.060.06 −25.48 0.31 0.12 10.46 0.25 0.31 0.22 0.00 SEQID-01733 0.03 0.030.05 0.05 0.04 0.03 0.03 0.08 −20.98 0.34 0.11 11.32 0.22 0.37 0.00 0.19SEQID-01734 0.04 0.07 0.03 0.04 0.05 0.01 0.04 0.07 −21.67 0.43 −0.025.11 0.21 0.33 0.00 0.21 SEQID-01735 0.03 0.05 0.00 0.04 0.04 0.02 0.090.03 −16.81 0.18 0.00 6.53 0.33 0.50 0.28 0.35 SEQID-01736 0.01 0.040.05 0.12 0.03 0.00 0.01 0.04 −31.20 0.13 −0.04 4.73 0.18 0.43 0.20 0.23SEQID-01737 0.02 0.03 0.06 0.03 0.04 0.01 0.02 0.06 −29.86 0.33 −0.044.86 0.19 0.36 0.19 0.18 SEQID-01738 0.02 0.04 0.07 0.06 0.04 0.00 0.030.05 −24.32 0.23 0.12 10.82 0.28 0.32 0.26 0.27 SEQID-01739 0.04 0.020.07 0.03 0.02 0.04 0.07 0.04 −16.56 0.35 0.03 8.54 0.36 0.53 0.24 0.25SEQID-01740 0.01 0.04 0.04 0.05 0.05 0.04 0.02 0.13 −17.37 0.51 −0.015.39 0.88 0.94 0.00 0.00 SEQID-01741 0.01 0.01 0.14 0.04 0.05 0.00 0.020.03 −23.90 0.14 0.23 11.53 0.26 0.40 0.27 0.28 SEQID-01742 0.03 0.030.02 0.06 0.05 0.01 0.07 0.04 −26.09 0.32 −0.06 4.46 0.23 0.31 0.00 0.00SEQID-01743 0.02 0.05 0.03 0.05 0.05 0.02 0.03 0.09 −18.35 0.48 0.006.53 0.22 0.35 0.23 0.23 SEQID-01744 0.02 0.02 0.04 0.06 0.02 0.00 0.050.04 −12.99 0.30 0.00 7.03 0.37 0.54 0.21 0.22 SEQID-01745 0.02 0.060.05 0.03 0.03 0.06 0.04 0.07 −20.06 0.31 −0.01 6.79 0.21 0.32 0.23 0.22SEQID-01746 0.02 0.02 0.01 0.07 0.05 0.00 0.02 0.04 −29.01 0.19 −0.094.37 0.22 0.39 0.18 0.18 SEQID-01747 0.04 0.06 0.03 0.07 0.08 0.02 0.050.02 −22.79 0.13 0.25 12.25 0.25 0.28 0.25 0.25 SEQID-01748 0.01 0.010.21 0.04 0.04 0.00 0.03 0.07 −6.36 0.48 0.03 8.08 0.33 0.41 0.29 0.24SEQID-01749 0.03 0.04 0.04 0.02 0.05 0.02 0.03 0.06 −25.48 0.20 0.1711.40 0.21 0.32 0.23 0.20 SEQID-01750 0.04 0.04 0.03 0.04 0.06 0.02 0.040.07 −20.83 0.49 −0.02 5.70 0.22 0.35 0.23 0.21 SEQID-01751 0.03 0.050.03 0.06 0.04 0.01 0.04 0.05 −25.28 0.31 0.02 9.52 0.21 0.33 0.20 0.21SEQID-01752 0.03 0.05 0.05 0.03 0.05 0.04 0.06 0.04 −20.99 0.33 0.029.01 0.16 0.35 0.17 0.18 SEQID-01753 0.02 0.03 0.01 0.02 0.06 0.00 0.060.07 −23.82 0.31 0.18 12.01 0.00 0.28 0.00 0.29 SEQID-01754 0.01 0.030.08 0.02 0.01 0.00 0.04 0.07 −24.56 0.26 0.17 11.38 0.24 0.28 0.25 0.25SEQID-01755 0.02 0.01 0.09 0.08 0.05 0.05 0.02 0.04 −14.26 0.60 0.017.87 0.49 0.59 0.25 1.00 SEQID-01756 0.02 0.07 0.05 0.06 0.03 0.05 0.040.07 −19.52 0.43 0.00 6.81 0.23 0.33 0.24 0.21 SEQID-01757 0.02 0.050.05 0.01 0.06 0.01 0.07 0.07 −21.11 0.37 0.00 7.15 0.20 0.34 0.00 0.00SEQID-01758 0.01 0.01 0.14 0.04 0.06 0.00 0.02 0.04 −23.91 0.15 0.2211.47 0.27 0.38 0.28 0.27 SEQID-01759 0.03 0.05 0.04 0.03 0.05 0.01 0.040.06 −22.82 0.35 0.10 10.82 0.21 0.31 0.00 0.00 SEQID-01760 0.04 0.050.04 0.03 0.07 0.03 0.02 0.07 −21.26 0.39 0.00 6.69 0.22 0.34 1.00 0.00SEQID-01761 0.02 0.06 0.07 0.08 0.05 0.03 0.03 0.09 −15.03 0.55 0.006.67 0.27 0.46 0.21 0.22 SEQID-01762 0.03 0.05 0.04 0.08 0.06 0.02 0.040.09 −17.42 0.45 0.02 8.86 0.61 0.88 0.00 0.21 SEQID-01763 0.02 0.030.03 0.05 0.05 0.01 0.03 0.04 −26.38 0.34 0.02 9.46 0.21 0.36 0.22 0.22SEQID-01764 0.03 0.08 0.03 0.05 0.06 0.00 0.00 0.07 −17.92 0.64 0.1210.11 0.32 0.32 0.30 0.31 SEQID-01765 0.02 0.05 0.04 0.03 0.07 0.00 0.020.04 −23.97 0.30 0.15 11.86 0.23 0.31 0.26 0.00 SEQID-01766 0.01 0.050.03 0.06 0.06 0.00 0.02 0.08 −23.42 0.37 −0.03 5.87 0.25 0.30 0.00 0.21SEQID-01767 0.04 0.07 0.05 0.04 0.02 0.06 0.05 0.08 −19.94 0.40 0.007.76 0.27 0.32 0.00 0.24 SEQID-01768 0.01 0.04 0.03 0.04 0.04 0.01 0.040.04 −29.34 0.19 0.22 11.43 0.23 0.31 0.23 0.24 SEQID-01769 0.02 0.070.06 0.04 0.04 0.01 0.04 0.04 −20.43 0.34 −0.03 5.16 0.26 0.33 0.22 0.21SEQID-01770 0.02 0.04 0.05 0.04 0.04 0.01 0.04 0.08 −19.28 0.34 0.1311.66 0.00 0.35 0.22 0.24 SEQID-01771 0.04 0.03 0.05 0.06 0.05 0.02 0.030.10 −17.25 0.53 −0.01 5.98 0.25 0.34 0.19 0.22 SEQID-01772 0.03 0.070.06 0.04 0.04 0.03 0.06 0.08 −22.03 0.34 −0.01 6.42 0.22 0.36 0.00 0.20SEQID-01773 0.03 0.04 0.03 0.05 0.04 0.02 0.05 0.07 −19.84 0.40 −0.024.95 0.89 0.98 0.22 0.22 SEQID-01774 0.02 0.05 0.05 0.05 0.03 0.01 0.060.05 −18.41 0.45 0.00 6.62 0.21 0.33 0.00 0.22 SEQID-01775 0.05 0.050.04 0.04 0.05 0.02 0.04 0.07 −20.94 0.40 −0.01 6.28 0.19 0.33 0.00 0.21SEQID-01776 0.05 0.02 0.05 0.03 0.05 0.00 0.01 0.06 −28.61 0.28 0.2412.14 0.26 0.31 0.21 0.20 SEQID-01777 0.03 0.08 0.04 0.03 0.05 0.01 0.010.11 −19.18 0.65 −0.01 6.67 0.60 0.69 0.25 0.20 SEQID-01778 0.02 0.020.07 0.02 0.03 0.04 0.05 0.10 −14.55 0.53 0.05 10.62 0.37 0.41 0.28 1.00SEQID-01779 0.03 0.08 0.01 0.08 0.03 0.01 0.05 0.06 −24.77 0.26 −0.015.29 0.22 0.29 0.21 0.23 SEQID-01780 0.03 0.06 0.05 0.02 0.03 0.01 0.050.07 −21.15 0.33 0.18 11.37 0.23 0.30 0.00 0.19 SEQID-01781 0.01 0.070.04 0.05 0.05 0.01 0.04 0.06 −21.09 0.35 0.17 11.28 0.25 0.30 0.21 0.22SEQID-01782 0.04 0.05 0.02 0.03 0.05 0.02 0.02 0.06 −26.59 0.30 0.1311.42 0.25 0.33 0.20 0.20 SEQID-01783 0.13 0.00 0.07 0.05 0.03 0.01 0.120.04 −6.89 0.52 0.01 8.00 0.26 0.34 0.00 0.23 SEQID-01784 0.04 0.07 0.040.03 0.06 0.03 0.08 0.05 −21.92 0.25 0.15 11.07 0.23 0.28 0.00 0.00SEQID-01785 0.02 0.05 0.03 0.03 0.02 0.01 0.05 0.06 −25.46 0.28 0.1010.94 0.21 0.33 0.00 0.00 SEQID-01786 0.02 0.06 0.02 0.05 0.06 0.02 0.040.03 −22.05 0.39 0.01 8.44 0.00 0.30 0.20 0.24 SEQID-01787 0.03 0.050.04 0.04 0.02 0.01 0.05 0.06 −23.74 0.25 0.13 10.91 0.21 0.31 0.00 0.25SEQID-01788 0.02 0.08 0.04 0.08 0.05 0.01 0.02 0.08 −17.07 0.47 0.039.88 0.24 0.81 0.00 0.24 SEQID-01789 0.04 0.04 0.04 0.02 0.03 0.03 0.040.10 −11.71 0.93 0.04 10.01 0.23 0.35 0.26 0.24 SEQID-01790 0.03 0.050.02 0.04 0.05 0.02 0.03 0.08 −25.32 0.30 0.08 10.48 0.21 0.31 0.00 0.00SEQID-01791 0.04 0.07 0.05 0.04 0.05 0.01 0.02 0.09 −18.66 0.49 0.006.72 0.24 0.32 0.00 0.22 SEQID-01792 0.03 0.03 0.04 0.05 0.04 0.00 0.050.07 −18.93 0.46 −0.01 5.90 0.21 0.37 0.00 0.23 SEQID-01793 0.02 0.040.05 0.05 0.06 0.00 0.04 0.08 −18.17 0.47 −0.01 6.37 0.22 0.33 0.00 0.22SEQID-01794 0.04 0.08 0.04 0.05 0.04 0.03 0.07 0.06 −19.95 0.32 −0.026.31 0.19 0.32 0.00 0.21 SEQID-01795 0.01 0.01 0.04 0.05 0.07 0.00 0.070.08 −25.22 0.20 0.25 11.95 0.25 0.30 0.26 0.25 SEQID-01796 0.02 0.020.03 0.05 0.04 0.00 0.03 0.05 −28.89 0.26 0.24 11.90 0.24 0.31 0.27 0.25SEQID-01797 0.06 0.04 0.03 0.04 0.06 0.01 0.03 0.06 −11.76 0.85 0.0310.18 0.58 0.79 0.30 0.23 SEQID-01798 0.05 0.03 0.06 0.01 0.05 0.00 0.030.10 −26.63 0.40 0.01 8.46 0.39 0.52 0.23 0.25 SEQID-01799 0.05 0.050.05 0.05 0.06 0.02 0.05 0.05 −21.19 0.26 0.00 6.94 0.22 0.32 0.22 0.22SEQID-01800 0.01 0.09 0.03 0.08 0.05 0.01 0.06 0.06 −19.85 0.36 0.018.43 0.22 0.33 0.22 0.25 SEQID-01801 0.01 0.04 0.02 0.04 0.02 0.01 0.100.03 −18.98 0.10 −0.01 6.26 0.29 0.49 0.28 0.32 SEQID-01802 0.03 0.060.05 0.03 0.05 0.00 0.02 0.08 −22.83 0.42 0.16 12.03 0.00 0.30 0.00 0.24SEQID-01803 0.04 0.04 0.03 0.03 0.03 0.03 0.04 0.05 −14.04 0.78 −0.016.41 0.25 0.34 0.25 0.24 SEQID-01804 0.01 0.07 0.06 0.05 0.03 0.04 0.070.05 −16.72 0.46 −0.01 5.64 0.25 0.31 0.00 0.00 SEQID-01805 0.04 0.050.03 0.04 0.04 0.01 0.04 0.09 −21.68 0.44 0.05 10.22 0.23 0.30 0.00 0.00SEQID-01806 0.03 0.03 0.06 0.05 0.04 0.01 0.02 0.06 −23.13 0.34 0.017.97 0.00 0.31 0.23 0.00 SEQID-01807 0.02 0.04 0.05 0.02 0.04 0.02 0.020.07 −24.75 0.37 0.14 11.12 0.00 0.31 0.24 0.21 SEQID-01808 0.01 0.080.04 0.05 0.05 0.03 0.07 0.08 −11.36 0.94 0.01 7.97 0.23 0.33 0.00 0.21SEQID-01809 0.02 0.06 0.05 0.03 0.07 0.02 0.02 0.09 −20.81 0.41 0.0810.85 0.23 0.33 0.20 0.26 SEQID-01810 0.04 0.08 0.04 0.04 0.05 0.02 0.050.07 −14.40 0.53 0.05 10.22 0.22 0.31 0.00 0.15 SEQID-01811 0.02 0.050.03 0.04 0.04 0.00 0.08 0.04 −26.68 0.27 0.04 9.78 0.19 0.37 0.00 0.23SEQID-01812 0.02 0.05 0.05 0.06 0.04 0.00 0.05 0.09 −21.32 0.56 −0.024.93 0.23 0.49 0.00 0.00 SEQID-01813 0.02 0.07 0.07 0.09 0.07 0.01 0.030.09 −9.80 0.68 0.00 7.68 0.22 0.32 0.22 0.21 SEQID-01814 0.03 0.09 0.030.06 0.03 0.02 0.07 0.05 −16.57 0.45 0.06 10.35 0.21 0.33 0.00 0.21SEQID-01815 0.04 0.08 0.04 0.06 0.04 0.07 0.02 0.07 −17.44 0.77 0.0510.58 0.21 0.32 0.18 0.19 SEQID-01816 0.03 0.07 0.05 0.07 0.05 0.02 0.040.09 −11.10 0.84 0.06 10.53 0.21 0.31 0.00 0.22 SEQID-01817 0.05 0.080.05 0.09 0.04 0.04 0.05 0.08 −11.63 0.77 0.04 10.12 0.21 0.30 0.00 0.20SEQID-01818 0.04 0.04 0.06 0.06 0.06 0.03 0.04 0.08 −17.52 0.45 −0.016.14 0.25 0.32 0.00 0.24 SEQID-01819 0.02 0.08 0.04 0.03 0.03 0.02 0.030.06 −23.99 0.39 0.00 6.74 0.23 0.32 0.00 0.22 SEQID-01820 0.03 0.060.05 0.06 0.06 0.04 0.07 0.06 −17.01 0.43 0.01 8.42 0.22 0.31 0.00 0.22SEQID-01821 0.01 0.05 0.05 0.05 0.04 0.01 0.03 0.08 −20.56 0.44 −0.024.99 0.21 0.34 0.00 0.22 SEQID-01822 0.03 0.09 0.03 0.06 0.05 0.01 0.060.07 −12.55 0.92 0.02 9.11 0.20 0.33 0.00 0.22 SEQID-01823 0.03 0.050.05 0.04 0.04 0.01 0.06 0.05 −19.29 0.44 −0.02 5.12 0.21 0.30 0.00 0.21SEQID-01824 0.02 0.04 0.04 0.05 0.05 0.00 0.02 0.09 −17.75 0.51 0.007.07 0.21 0.35 0.20 0.22 SEQID-01825 0.03 0.07 0.01 0.03 0.04 0.05 0.080.05 −18.27 0.71 0.09 10.32 0.31 0.28 0.00 0.00 SEQID-01826 0.06 0.020.02 0.06 0.10 0.02 0.02 0.16 −18.59 0.39 −0.01 5.02 0.30 0.30 0.26 0.24SEQID-01827 0.05 0.12 0.06 0.05 0.04 0.00 0.05 0.06 −14.20 0.51 −0.026.07 0.53 0.60 0.00 0.22 SEQID-01828 0.02 0.02 0.03 0.04 0.03 0.00 0.040.06 −18.73 0.48 0.08 10.91 0.24 0.30 0.31 0.22 SEQID-01829 0.01 0.030.07 0.02 0.01 0.00 0.03 0.07 −23.75 0.29 0.17 11.60 0.23 0.30 0.23 0.26SEQID-01830 0.03 0.04 0.06 0.04 0.07 0.01 0.01 0.10 −19.88 0.43 0.029.21 0.26 0.34 0.16 0.26 SEQID-01831 0.03 0.05 0.04 0.04 0.03 0.00 0.010.06 −23.32 0.35 0.09 11.36 0.24 0.32 0.00 0.23 SEQID-01832 0.02 0.040.05 0.04 0.02 0.02 0.06 0.07 −21.28 0.28 0.07 10.53 0.22 0.30 0.20 0.21SEQID-01833 0.05 0.02 0.04 0.06 0.03 0.01 0.03 0.12 −18.22 0.58 0.007.15 0.19 0.31 0.24 0.25 SEQID-01334 0.02 0.05 0.05 0.02 0.05 0.00 0.070.07 −23.53 0.36 0.15 11.29 0.24 0.31 0.00 0.21 SEQID-01835 0.01 0.090.05 0.07 0.05 0.03 0.00 0.07 −25.23 0.26 −0.01 5.78 0.74 0.88 0.00 0.28SEQID-01836 0.03 0.03 0.04 0.02 0.04 0.03 0.04 0.05 −18.59 0.62 −0.044.41 0.27 0.35 0.21 0.25 SEQID-01837 0.01 0.02 0.05 0.03 0.05 0.02 0.040.06 −19.08 0.62 −0.01 6.25 0.27 0.32 0.26 0.25 SEQID-01838 0.02 0.030.06 0.03 0.06 0.01 0.05 0.10 −21.38 0.32 0.12 11.06 0.22 0.28 0.00 0.25SEQID-01839 0.03 0.06 0.01 0.03 0.07 0.04 0.04 0.06 −20.86 0.45 0.006.80 0.22 0.31 0.00 0.25 SEQID-01840 0.04 0.04 0.05 0.04 0.04 0.03 0.060.07 −18.59 0.47 −0.02 5.34 0.25 0.33 0.21 0.23 SEQID-01841 0.02 0.070.06 0.05 0.05 0.01 0.03 0.07 −24.15 0.39 0.10 10.85 0.23 0.31 0.00 0.00SEQID-01842 0.04 0.01 0.04 0.03 0.03 0.02 0.05 0.06 −25.12 0.36 0.1310.87 0.20 0.31 0.20 0.00 SEQID-01843 0.03 0.06 0.01 0.06 0.05 0.02 0.050.10 −23.04 0.39 −0.01 5.80 0.20 0.29 0.00 0.00 SEQID-01844 0.03 0.040.06 0.05 0.02 0.01 0.07 0.07 −23.20 0.42 −0.02 5.39 0.22 0.33 0.20 0.22SEQID-01845 0.04 0.05 0.06 0.03 0.07 0.01 0.04 0.07 −21.00 0.36 0.006.79 0.81 0.91 0.23 0.20 SEQID-01846 0.02 0.03 0.04 0.04 0.03 0.05 0.060.07 −16.96 0.39 0.00 7.32 0.75 0.94 0.21 0.00 SEQID-01847 0.02 0.080.05 0.07 0.04 0.01 0.04 0.08 −16.06 0.59 −0.01 6.23 0.23 0.33 0.24 0.00SEQID-01848 0.02 0.02 0.04 0.07 0.07 0.00 0.04 0.12 −19.65 0.63 0.018.90 0.17 0.34 0.23 0.00 SEQID-01849 0.03 0.05 0.04 0.06 0.04 0.03 0.050.05 −18.97 0.54 0.02 9.46 0.24 0.31 0.20 0.23 SEQID-01850 0.01 0.070.05 0.05 0.04 0.03 0.08 0.06 −12.44 0.40 0.04 8.62 0.51 0.65 0.19 0.24SEQID-01851 0.02 0.04 0.03 0.02 0.01 0.01 0.06 0.06 −25.38 0.30 0.1010.72 0.23 0.33 0.22 0.00 SEQID-01852 0.02 0.06 0.06 0.08 0.02 0.01 0.050.04 −15.19 0.11 0.01 7.81 0.29 0.49 0.23 0.29 SEQID-01853 0.00 0.000.38 0.04 0.20 0.00 0.09 0.01 −12.64 0.12 0.10 10.61 0.26 0.54 0.29 0.25SEQID-01854 0.04 0.05 0.05 0.05 0.02 0.01 0.04 0.08 −19.12 0.53 −0.015.47 0.21 0.33 0.00 0.00 SEQID-01855 0.03 0.08 0.04 0.05 0.04 0.02 0.020.07 −18.77 0.58 −0.02 5.23 0.00 0.33 0.00 0.19 SEQID-01856 0.03 0.050.05 0.07 0.05 0.00 0.03 0.09 −17.27 0.52 0.00 8.03 0.53 0.71 0.00 0.22SEQID-01857 0.03 0.05 0.04 0.04 0.05 0.02 0.03 0.11 −17.00 0.54 0.006.82 0.28 0.35 0.20 0.21 SEQID-01858 0.03 0.07 0.06 0.06 0.03 0.01 0.040.08 −16.63 0.53 0.01 8.46 0.22 0.35 0.00 0.22 SEQID-01859 0.03 0.060.05 0.05 0.05 0.01 0.04 0.07 −17.33 0.54 0.01 7.73 0.22 0.33 0.20 0.22SEQID-01860 0.03 0.05 0.04 0.04 0.04 0.02 0.04 0.09 −20.27 0.38 −0.025.18 0.22 0.34 0.22 0.23 SEQID-01861 0.04 0.09 0.04 0.06 0.04 0.03 0.050.06 −12.27 0.91 0.03 9.53 0.20 0.33 0.00 0.21 SEQID-01862 0.02 0.030.05 0.05 0.07 0.01 0.03 0.07 −19.54 0.41 0.00 7.45 0.21 0.34 0.18 0.21SEQID-01863 0.03 0.04 0.03 0.04 0.06 0.01 0.03 0.06 −23.07 0.38 −0.034.84 0.71 0.91 0.00 0.20 SEQID-01864 0.03 0.07 0.04 0.05 0.05 0.03 0.040.07 −18.51 0.52 0.02 9.23 0.19 0.33 0.20 0.20 SEQID-01865 0.03 0.040.01 0.04 0.05 0.01 0.03 0.04 −28.16 0.23 −0.02 5.50 0.18 0.58 0.18 0.18SEQID-01866 0.03 0.04 0.01 0.04 0.05 0.01 0.03 0.04 −28.15 0.23 −0.025.56 0.18 0.55 0.18 0.17 SEQID-01867 0.03 0.04 0.01 0.04 0.04 0.01 0.030.04 −28.30 0.23 −0.02 5.50 0.19 0.55 0.18 0.17 SEQID-01868 0.03 0.040.01 0.04 0.04 0.01 0.03 0.04 −28.42 0.22 −0.02 5.48 0.18 0.53 0.18 0.19SEQID-01869 0.05 0.04 0.04 0.05 0.06 0.02 0.06 0.05 −19.69 0.41 −0.035.05 0.19 0.30 0.00 0.20 SEQID-01870 0.02 0.04 0.06 0.05 0.08 0.01 0.040.08 −22.75 0.31 0.01 8.67 0.18 0.35 0.18 0.19 SEQID-01871 0.03 0.060.03 0.03 0.04 0.02 0.06 0.06 −22.38 0.34 0.00 7.11 0.19 0.31 0.00 0.20SEQID-01872 0.03 0.04 0.03 0.03 0.04 0.03 0.04 0.03 −24.32 0.29 −0.035.13 0.20 0.36 0.00 0.20 SEQID-01873 0.03 0.05 0.04 0.04 0.04 0.02 0.040.07 −23.56 0.32 0.00 7.11 0.42 0.64 0.00 0.00 SEQID-01874 0.00 0.070.04 0.03 0.04 0.01 0.05 0.05 −24.99 0.33 −0.01 6.33 0.80 0.90 0.00 0.22SEQID-01875 0.03 0.05 0.03 0.04 0.04 0.01 0.04 0.07 −20.83 0.43 0.018.12 0.85 0.99 0.21 0.22 SEQID-01876 0.04 0.05 0.04 0.04 0.06 0.02 0.090.08 −19.08 0.62 −0.02 4.92 0.19 0.35 0.18 0.20 SEQID-01877 0.04 0.040.04 0.04 0.05 0.01 0.09 0.08 −20.69 0.45 0.01 7.94 0.22 0.31 0.00 0.22SEQID-01878 0.04 0.04 0.03 0.03 0.04 0.03 0.09 0.04 −23.47 0.31 −0.035.12 0.21 0.34 0.00 0.20 SEQID-01879 0.04 0.06 0.03 0.05 0.06 0.02 0.040.09 −17.84 0.47 0.02 8.58 0.69 0.85 0.00 0.21 SEQID-01880 0.04 0.060.04 0.05 0.06 0.03 0.03 0.08 −18.26 0.64 −0.02 4.99 0.18 0.35 0.19 0.20SEQID-01881 0.02 0.04 0.06 0.05 0.05 0.03 0.05 0.07 −23.52 0.30 −0.016.23 0.19 0.33 0.19 0.20 SEQID-01882 0.01 0.02 0.18 0.03 0.03 0.01 0.020.04 −13.80 0.20 0.01 9.54 0.95 1.00 0.21 0.39 SEQID-01883 0.04 0.030.03 0.05 0.04 0.01 0.09 0.04 −24.90 0.20 0.04 9.62 0.18 0.33 0.19 0.18SEQID-01884 0.01 0.08 0.03 0.04 0.05 0.02 0.07 0.06 −21.41 0.25 0.078.46 0.22 0.30 0.21 0.23 SEQID-01885 0.04 0.06 0.06 0.03 0.03 0.00 0.020.05 −23.23 0.36 −0.04 4.61 0.33 0.46 0.00 0.25 SEQID-01886 0.01 0.040.04 0.03 0.05 0.03 0.02 0.09 −19.17 0.44 0.00 7.03 0.65 0.384 0.00 0.22SEQID-01887 0.03 0.05 0.05 0.04 0.04 0.02 0.04 0.06 −21.09 0.44 −0.044.95 0.00 0.41 0.00 0.18 SEQID-01888 0.03 0.09 0.02 0.04 0.03 0.03 0.060.07 −16.87 0.54 0.07 10.33 0.21 0.34 0.00 0.00 SEQID-01889 0.05 0.090.03 0.02 0.05 0.01 0.02 0.05 −25.05 0.32 −0.04 4.61 0.41 0.59 0.25 0.23SEQID-01890 0.04 0.05 0.04 0.05 0.03 0.02 0.01 0.08 −20.27 0.44 0.018.04 0.22 0.35 0.21 0.22 SEQID-01891 0.02 0.05 0.05 0.06 0.05 0.03 0.050.098 −22.19 0.34 −0.03 5.09 0.19 0.34 0.19 0.18 SEQID-01892 0.03 0.030.03 0.05 0.03 0.03 0.03 0.10 −18.61 0.56 0.01 8.23 0.23 0.31 0.00 0.21SEQID-01893 0.02 0.05 0.06 0.04 0.05 0.02 0.04 0.09 −23.86 0.90 0.006.49 0.19 0.35 0.19 0.20 SEQID-01894 0.01 0.05 0.07 0.05 0.05 0.05 0.060.05 −20.39 0.32 0.02 7.97 0.22 0.31 0.00 0.22 SEQID-01895 0.04 0.030.05 0.03 0.05 0.05 0.03 0.04 −23.30 0.27 0.02 9.08 0.21 0.30 0.21 0.20SEQID-01896 0.02 0.02 0.03 0.05 0.05 0.02 0.09 0.06 −25.22 0.18 0.049.62 0.00 0.34 0.18 0.18 SEQID-01897 0.02 0.04 0.02 0.06 0.05 0.00 0.090.05 −25.35 0.18 −0.03 4.94 0.30 0.45 0.20 0.22 SEQID-01898 0.03 0.070.04 0.05 0.05 0.01 0.05 0.06 −19.06 0.48 0.00 7.01 0.21 0.32 0.00 0.22SEQID-01899 0.04 0.04 0.02 0.04 0.07 0.02 0.03 0.07 −19.21 0.46 0.018.28 0.20 0.34 0.00 0.20 SEQID-01900 0.02 0.04 0.04 0.06 0.05 0.03 0.060.07 −22.22 0.31 −0.01 6.46 0.18 0.35 0.19 0.19 SEQID-01901 0.04 0.050.06 0.09 0.05 0.01 0.05 0.04 −17.28 0.20 0.01 8.67 0.24 0.40 0.25 0.25SEQID-01902 0.02 0.01 0.03 0.02 0.01 0.01 0.03 0.03 −38.43 0.07 −0.016.36 0.23 0.36 0.23 0.23 SEQID-01903 0.03 0.08 0.06 0.05 0.04 0.02 0.070.07 −15.95 0.55 0.04 9.68 0.20 0.34 0.00 0.21 SEQID-01904 0.02 0.060.03 0.04 0.06 0.03 0.05 0.06 −21.24 0.34 0.02 8.76 0.21 0.31 0.00 0.21SEQID-01905 0.02 0.05 0.07 0.05 0.07 0.01 0.04 0.09 −18.84 0.32 −0.025.81 0.00 0.39 0.17 0.22 SEQID-01906 0.03 0.05 0.04 0.04 0.05 0.02 0.040.06 −22.41 0.34 0.01 8.31 0.37 0.56 0.00 0.20 SEQID-01907 0.03 0.070.04 0.05 0.06 0.04 0.03 0.05 −19.24 0.41 0.01 8.17 0.20 0.33 0.00 0.21SEQID-01908 0.04 0.00 0.00 0.03 0.03 0.00 0.02 0.03 −36.92 0.12 −0.114.32 0.55 0.68 0.23 0.25 SEQID-01909 0.02 0.04 0.03 0.05 0.05 0.00 0.050.07 −19.57 0.43 0.01 9.19 0.21 0.32 0.00 0.21 SEQID-01910 0.02 0.040.05 0.04 0.05 0.02 0.04 0.05 −19.81 0.39 0.01 8.14 0.20 0.33 0.00 0.21SEQID-01911 0.02 0.03 0.04 0.06 0.07 0.02 0.02 0.10 −20.99 0.34 −0.016.28 0.21 0.32 0.19 0.21 SEQID-01912 0.01 0.07 0.04 0.06 0.05 0.01 0.020.08 −16.91 0.42 0.03 9.14 0.24 0.31 0.00 0.26 SEQID-01913 0.02 0.070.02 0.03 0.01 0.02 0.02 0.12 −18.96 0.49 0.01 7.84 0.25 0.31 0.24 0.26SEQID-01914 0.01 0.10 0.089 0.07 0.04 0.02 0.02 0.05 −23.35 0.27 0.017.38 0.24 0.35 0.23 0.24 SEQID-01915 0.03 0.02 0.24 0.03 0.01 0.00 0.000.02 −12.61 0.11 0.02 10.55 0.70 0.80 0.31 0.48 SEQID-01916 0.04 0.010.03 0.04 0.03 0.02 0.02 0.05 −30.81 0.23 0.07 10.38 0.26 0.33 0.00 0.21SEQID-01917 0.01 0.04 0.13 0.05 0.02 0.01 0.04 0.08 −16.73 0.44 −0.016.39 0.27 0.33 0.29 0.27 SEQID-01918 0.04 0.11 0.04 0.02 0.05 0.00 0.020.05 −26.07 0.31 −0.05 4.56 0.41 0.60 0.00 0.00 SEQID-01919 0.03 0.050.06 0.05 0.06 0.00 0.02 0.08 −16.12 0.56 0.02 8.90 0.51 0.69 0.22 0.21SEQID-01920 0.03 0.04 0.03 0.06 0.04 0.02 0.03 0.08 −20.62 0.54 0.006.53 0.25 0.33 0.17 0.00 SEQID-01921 0.01 0.03 0.05 0.04 0.04 0.01 0.050.07 −19.18 0.43 0.00 6.63 0.20 0.33 0.00 0.21 SEQID-01922 0.03 0.040.05 0.04 0.06 0.00 0.04 0.08 −17.78 0.51 −0.03 4.92 0.22 0.33 0.23 0.22SEQID-01923 0.02 0.05 0.08 0.06 0.03 0.01 0.03 0.03 −23.01 0.25 −0.094.22 0.23 0.40 0.20 0.23 SEQID-01924 0.02 0.04 0.05 0.05 0.04 0.03 0.090.03 −22.92 0.44 0.01 7.66 0.20 0.28 0.21 0.22 SEQID-01925 0.01 0.030.21 0.04 0.03 0.01 0.01 0.03 −13.36 0.14 0.00 5.29 0.50 0.73 0.29 0.46SEQID-01926 0.04 0.06 0.03 0.03 0.04 0.00 0.02 0.07 −17.97 0.56 −0.035.11 0.22 0.30 0.00 0.23 SEQID-01927 0.04 0.05 0.04 0.05 0.06 0.02 0.030.09 −20.09 0.45 0.04 9.88 0.21 0.33 0.00 0.21 SEQID-01928 0.02 0.040.06 0.04 0.02 0.03 0.02 0.07 −20.39 0.43 −0.01 6.51 0.22 0.34 0.22 0.23SEQID-01929 0.02 0.04 0.01 0.04 0.05 0.01 0.04 0.04 −28.64 0.25 −0.016.48 0.22 0.40 0.00 0.20 SEQID-01930 0.03 0.05 0.05 0.05 0.04 0.03 0.060.05 −19.50 0.38 0.00 6.80 0.19 0.35 0.18 0.19 SEQID-01931 0.02 0.040.04 0.04 0.06 0.02 0.05 0.06 −18.28 0.41 0.02 8.47 0.24 0.31 0.00 0.20SEQID-01932 0.03 0.05 0.03 0.05 0.06 0.03 0.05 0.10 −18.27 0.46 0.028.91 0.69 0.84 0.00 0.22 SEQID-01933 0.02 0.04 0.04 0.05 0.06 0.02 0.050.05 −18.20 0.40 0.02 8.61 0.24 0.31 0.00 0.20 SEQID-01934 0.02 0.050.03 0.04 0.03 0.01 0.04 0.06 −21.81 0.39 0.00 7.27 0.98 1.00 0.21 0.21SEQID-01935 0.02 0.05 0.03 0.04 0.04 0.01 0.04 0.06 −21.72 0.38 0.007.09 1.00 1.00 0.20 0.22 SEQID-01936 0.05 0.04 0.04 0.05 0.06 0.02 0.060.05 −19.65 0.42 −0.03 5.05 0.19 0.30 0.00 0.19 SEQID-01937 0.04 0.060.04 0.04 0.05 0.02 0.03 0.06 −23.67 0.30 0.00 6.93 0.43 0.61 0.00 0.21SEQID-01938 0.02 0.04 0.03 0.04 0.04 0.04 0.02 0.09 −19.79 0.43 0.017.89 0.68 0.76 0.22 0.00 SEQID-01939 0.05 0.06 0.04 0.04 0.04 0.02 0.030.06 −23.33 0.31 0.00 6.92 0.43 0.64 0.00 0.20 SEQID-01940 0.02 0.000.00 0.04 0.04 0.00 0.03 0.03 −36.46 0.13 −0.10 4.34 0.58 0.68 0.25 0.22SEQID-01941 0.04 0.04 0.03 0.04 0.05 0.01 0.03 0.06 −21.67 0.42 0.018.12 0.20 0.35 0.00 0.22 SEQID-01942 0.05 0.06 0.07 0.02 0.03 0.00 0.020.07 −23.48 0.34 −0.06 4.40 0.28 0.37 0.00 0.24 SEQID-01943 0.04 0.060.03 0.03 0.03 0.02 0.06 0.06 −22.73 0.34 0.00 7.18 0.20 0.33 0.00 0.20SEQID-01944 0.04 0.06 0.03 0.04 0.04 0.01 0.01 0.08 −20.06 0.45 0.018.29 0.22 0.35 0.00 0.21 SEQID-01945 0.05 0.06 0.07 0.02 0.03 0.00 0.020.07 −23.48 0.34 −0.06 4.40 0.28 0.37 0.00 0.24 SEQID-01946 0.04 0.090.03 0.04 0.04 0.01 0.03 0.06 −23.98 0.39 −0.06 4.41 0.41 0.54 0.00 0.23SEQID-01947 0.04 0.03 0.04 0.03 0.05 0.05 0.03 0.04 −22.93 0.30 0.039.29 0.21 0.30 0.20 0.00 SEQID-01948 0.09 0.01 0.01 0.04 0.02 0.01 0.010.05 −31.88 0.29 0.04 10.04 0.28 0.36 0.22 0.25 SEQID-01949 0.04 0.030.03 0.04 0.04 0.00 0.05 0.07 −25.50 0.40 0.01 8.17 0.00 0.33 0.00 0.21SEQID-01950 0.02 0.03 0.09 0.03 0.07 0.02 0.04 0.07 −22.65 0.29 −0.015.76 0.21 0.44 0.00 0.23 SEQID-01951 0.02 0.14 0.01 0.02 0.05 0.00 0.000.04 −24.37 0.45 −0.04 4.73 1.00 1.00 0.24 0.22 SEQID-01952 0.04 0.020.03 0.03 0.06 0.00 0.02 0.10 −20.88 0.50 −0.01 5.38 0.20 0.35 0.19 0.22SEQID-01953 0.01 0.02 0.04 0.03 0.02 0.01 0.01 0.04 −39.35 0.11 −0.035.20 0.24 0.40 0.23 0.25 SEQID-01954 0.04 0.06 0.03 0.02 0.06 0.01 0.010.09 −19.05 0.60 0.00 6.97 0.22 0.32 0.00 0.22 SEQID-01955 0.03 0.040.04 0.04 0.06 0.02 0.04 0.08 −20.42 0.45 0.03 9.75 0.21 0.31 0.00 0.21SEQID-01956 0.04 0.05 0.02 0.04 0.05 0.02 0.04 0.04 −22.36 0.29 −0.074.39 0.20 0.34 0.00 0.21 SEQID-01957 0.04 0.09 0.02 0.05 0.04 0.03 0.060.05 −16.87 0.53 0.06 10.30 0.20 0.31 0.00 0.20 SEQID-01958 0.03 0.060.04 0.04 0.06 0.03 0.06 0.06 −20.42 0.37 0.01 7.71 0.21 0.34 0.00 0.20SEQID-01959 0.04 0.05 0.04 0.04 0.06 0.02 0.03 0.05 −21.88 0.34 0.017.73 0.37 0.59 0.00 0.21 SEQID-01960 0.03 0.03 0.04 0.05 0.05 0.00 0.040.08 −18.98 0.44 0.02 9.29 0.21 0.33 0.19 0.22 SEQID-01961 0.03 0.070.04 0.05 0.05 0.01 0.05 0.07 −18.96 0.44 0.00 7.19 0.21 0.33 0.00 0.21SEQID-01962 0.02 0.07 0.04 0.06 0.05 0.01 0.07 0.06 −19.47 0.32 0.019.19 0.20 0.33 0.00 0.20 SEQID-01963 0.02 0.07 0.04 0.06 0.05 0.01 0.070.06 −19.50 0.32 0.01 9.03 0.20 0.33 0.00 0.20 SEQID-01964 0.04 0.020.03 0.03 0.06 0.00 0.02 0.07 −22.39 0.45 −0.03 4.71 0.21 0.34 0.22 0.22SEQID-01965 0.02 0.02 0.06 0.07 0.05 0.00 0.02 0.08 −22.73 0.33 −0.025.25 0.19 0.34 0.20 0.20 SEQID-01966 0.02 0.02 0.05 0.05 0.05 0.00 0.010.08 −23.32 0.37 −0.02 5.11 0.20 0.36 0.00 0.21 SEQID-01967 0.03 0.060.04 0.04 0.04 0.01 0.05 0.08 −21.62 0.44 −0.03 4.79 0.19 0.32 0.00 0.22SEQID-01968 0.03 0.06 0.04 0.04 0.04 0.01 0.05 0.08 −21.87 0.43 −0.034.88 0.20 0.33 0.00 0.22 SEQID-01969 0.05 0.04 0.03 0.04 0.0J 0.01 0.020.07 −19.58 0.53 −0.03 5.04 0.18 0.32 0.20 0.22 SEQID-01970 0.04 0.030.04 0.05 0.05 0.00 0.05 0.07 −18.79 0.41 −0.02 6.01 0.20 0.31 0.00 0.20SEQID-01971 0.02 0.04 0.05 0.04 0.06 0.03 0.01 0.05 −22.65 0.19 0.029.92 0.21 0.33 0.17 0.00 SEQID-01972 0.01 0.04 0.04 0.04 0.03 0.03 0.070.05 −20.52 0.33 −0.03 4.96 0.18 0.36 0.19 0.19 SEQID-01973 0.01 0.030.05 0.09 0.05 0.02 0.04 0.06 −17.93 0.33 0.01 8.38 0.20 0.35 0.20 0.21SEQID-01974 0.03 0.02 0.03 0.05 0.07 0.03 0.04 0.10 −17.52 0.53 −0.016.51 0.46 0.62 0.00 0.20 SEQID-01975 0.03 0.02 0.03 0.05 0.07 0.03 0.040.10 −17.78 0.52 0.00 6.72 0.46 0.62 0.00 0.19 SEQID-01976 0.03 0.070.06 0.04 0.06 0.03 0.07 0.05 −18.64 0.28 0.02 9.52 0.22 0.31 0.00 0.20SEQID-01977 0.03 0.09 0.04 0.05 0.05 0.06 0.04 0.05 −12.42 0.65 0.017.91 0.20 0.34 0.00 0.21 SEQID-01978 0.02 0.04 0.03 0.03 0.04 0.00 0.030.06 −24.74 0.39 −0.02 5.17 0.20 0.33 0.52 0.21 SEQID-01979 0.01 0.050.06 0.08 0.09 0.01 0.03 0.07 −13.51 0.41 0.00 6.95 0.20 0.37 0.20 0.20SEQID-01980 0.02 0.04 0.05 0.04 0.04 0.01 0.05 0.07 −22.92 0.34 −0.025.09 0.20 0.34 0.20 0.20 SEQID-01981 0.04 0.04 0.04 0.02 0.08 0.00 0.030.08 −22.02 0.46 −0.03 5.12 0.22 0.31 0.20 0.22 SEQID-01982 0.04 0.040.05 0.03 0.06 0.02 0.07 0.04 −19.89 0.33 0.00 6.79 0.21 0.34 0.00 0.00SEQID-01983 0.04 0.04 0.04 0.02 0.03 0.00 0.03 0.08 −21.44 0.46 −0.035.22 0.21 0.31 0.20 0.22 SEQID-01984 0.02 0.05 0.04 0.05 0.05 0.03 0.050.07 −18.58 0.45 −0.02 5.96 0.21 0.33 0.00 0.22 SEQID-01985 0.04 0.020.04 0.03 0.07 0.00 0.06 0.03 −24.96 0.23 0.02 8.66 0.00 0.30 0.21 0.25SEQID-01986 0.04 0.02 0.02 0.04 0.06 0.00 0.01 0.09 −20.21 0.51 −0.034.60 0.21 0.35 0.22 0.21 SEQID-01987 0.02 0.05 0.03 0.05 0.07 0.03 0.050.05 −20.16 0.29 −0.03 5.06 0.16 0.35 0.18 0.19 SEQID-01988 0.03 0.040.04 0.05 0.05 0.01 0.04 0.09 −21.92 0.44 −0.04 4.75 0.20 0.32 0.00 0.20SEQID-01989 0.02 0.03 0.04 0.04 0.06 0.01 0.03 0.08 −22.26 0.39 −0.064.33 0.19 0.34 0.20 0.20 SEQID-01990 0.05 0.10 0.05 0.04 0.05 0.03 0.030.10 −21.67 0.43 −0.03 4.62 0.35 0.46 0.00 0.23 SEQID-01991 0.03 0.050.03 0.05 0.04 0.02 0.0a 0.07 −19.43 0.27 0.01 9.01 0.23 0.32 0.00 0.23SEQID-01992 0.04 0.07 0.06 0.03 0.06 0.03 0.03 0.06 −16.92 0.43 −0.024.62 0.21 0.33 0.00 0.00 SEQID-01993 0.03 0.13 0.05 0.04 0.05 0.06 0.030.07 −14.71 0.55 −0.01 6.13 0.22 0.36 0.22 0.23 SEQID-01994 0.03 0.030.04 0.05 0.05 0.00 0.05 0.07 −18.50 0.48 −0.03 4.53 0.21 0.32 0.21 0.21SEQID-01995 0.04 0.01 0.02 0.04 0.06 0.00 0.01 0.09 −20.53 0.52 −0.034.70 0.22 0.34 0.22 0.21 SEQID-01996 0.03 0.07 0.04 0.05 0.04 0.01 0.050.06 −18.00 0.45 −0.02 5.27 0.19 0.33 0.00 0.22 SEQID-01997 0.02 0.050.03 0.05 0.06 0.03 0.05 0.05 −20.64 0.28 −0.03 4.99 0.16 0.35 0.18 0.19SEQID-01998 0.03 0.11 0.05 0.04 0.05 0.06 0.04 0.07 −14.37 0.56 −0.016.40 0.22 0.36 0.00 0.23 SEQID-01999 0.04 0.02 0.04 0.04 0.07 0.00 0.060.03 −24.83 0.23 0.02 8.66 0.24 0.31 0.00 0.00 SEQID-02000 0.03 0.070.05 0.03 0.07 0.01 0.05 0.04 −22.75 0.22 0.02 8.96 0.22 0.28 0.19 0.21SEQID-02001 0.05 0.03 0.03 0.06 0.06 0.00 0.08 0.08 −20.51 0.45 −0.034.60 0.00 0.31 0.26 0.24 SEQID-02002 0.02 0.05 0.03 0.08 0.05 0.01 0.090.06 −19.91 0.29 0.01 8.38 0.21 0.34 0.00 0.00 SEQID-02003 0.04 0.050.05 0.05 0.05 0.00 0.04 0.09 −18.47 0.49 −0.03 4.64 0.21 0.33 0.21 0.22SEQID-02004 0.02 0.03 0.04 0.04 0.07 0.00 0.02 0.08 −22.68 0.36 −0.044.52 0.49 0.78 0.00 0.21 SEQID-02005 0.03 0.07 0.04 0.05 0.04 0.01 0.050.06 −17.91 0.46 −0.03 5.03 0.21 0.33 0.00 0.22 SEQID-02006 0.03 0.090.04 0.04 0.05 0.07 0.06 0.05 −12.46 0.63 0.00 7.04 0.20 0.31 0.00 0.20SEQID-02007 0.01 0.03 0.02 0.07 0.05 0.00 0.03 0.02 −24.40 0.16 −0.034.85 0.22 0.39 0.00 0.19 SEQID-02008 0.04 0.02 0.02 0.06 0.06 0.00 0.110.06 −16.77 0.44 0.00 6.60 0.23 0.30 0.21 0.25 SEQID-02009 0.03 0.090.04 0.04 0.03 0.06 0.05 0.06 −12.75 0.69 −0.01 6.58 0.21 0.34 0.00 0.22SEQID-02010 0.03 0.05 0.04 0.03 0.04 0.03 0.07 0.05 −20.82 0.31 −0.026.11 0.20 0.34 0.00 0.20 SEQID-02011 0.03 0.04 0.05 0.05 0.04 0.02 0.040.06 −18.19 0.42 −0.02 5.59 0.20 0.34 0.20 0.21 SEQID-02012 0.01 0.040.03 0.07 0.06 0.00 0.04 0.03 −22.36 0.24 −0.01 5.90 0.22 0.35 0.19 0.21SEQID-02013 0.02 0.04 0.04 0.05 0.06 0.00 0.04 0.06 −20.36 0.41 −0.025.32 0.22 0.31 0.00 0.00 SEQID-02014 0.01 0.02 0.01 0.05 0.07 0.01 0.000.04 −24.24 0.09 −0.09 4.24 0.23 0.36 0.20 0.21 SEQID-02015 0.03 0.090.05 0.03 0.04 0.06 0.07 0.05 −20.47 0.34 −0.04 5.55 0.19 0.36 0.00 0.20SEQID-02016 0.01 0.00 0.24 0.06 0.07 0.00 0.00 0.04 −29.60 0.05 0.007.54 0.33 0.35 0.33 0.34 SEQID-02017 0.04 0.04 0.03 0.08 0.06 0.00 0.050.07 −16.22 0.56 −0.02 4.71 0.00 0.32 0.23 0.23 SEQID-02018 0.03 0.020.03 0.03 0.06 0.01 0.05 0.08 −23.78 0.41 −0.03 4.90 0.24 0.31 0.00 0.24SEQID-02019 0.04 0.10 0.04 0.06 0.04 0.05 0.06 0.07 −10.97 0.74 −0.025.24 0.21 0.31 0.00 0.20 SEQID-02020 0.02 0.06 0.04 0.03 0.05 0.01 0.020.07 −20.48 0.50 −0.02 5.04 0.21 0.33 0.21 0.23 SEQID-02021 0.04 0.030.02 0.03 0.04 0.01 0.02 0.07 −26.59 0.33 −0.01 5.56 0.22 0.34 0.19 0.00SEQID-02022 0.02 0.04 0.03 0.05 0.05 0.01 0.03 0.07 −21.00 0.39 0.008.02 0.21 0.33 0.00 0.00 SEQID-02023 0.04 0.04 0.03 0.03 0.07 0.01 0.030.08 −19.81 0.47 −0.02 5.81 0.22 0.32 0.00 0.21 SEQID-02024 0.03 0.050.05 0.04 0.04 0.04 0.06 0.05 −19.74 0.33 −0.02 6.18 0.19 0.33 0.00 0.20SEQID-02025 0.02 0.05 0.03 0.04 0.05 0.02 0.06 0.06 −21.52 0.37 −0.025.59 0.19 0.33 0.19 0.20 SEQID-02026 0.03 0.03 0.02 0.03 0.04 0.01 0.020.07 −27.34 0.28 −0.01 5.56 0.23 0.33 0.00 0.00 SEQID-02027 0.02 0.010.06 0.05 0.05 0.01 0.04 0.07 −21.18 0.31 0.13 11.71 0.25 0.35 0.21 0.24SEQID-02028 0.01 0.04 0.21 0.03 0.06 0.01 0.02 0.06 −24.60 0.34 −0.015.18 0.23 0.44 0.26 0.24 SEQID-02029 0.03 0.05 0.04 0.06 0.07 0.02 0.040.08 −18.14 0.47 −0.02 5.39 0.58 0.79 0.00 0.22 SEQID-02030 0.02 0.070.04 0.06 0.05 0.02 0.08 0.05 −18.45 0.35 0.00 7.05 0.23 0.32 0.00 0.22SEQID-02031 0.03 0.06 0.06 0.05 0.04 0.03 0.04 0.06 −19.68 0.41 −0.044.61 0.22 0.35 0.00 0.23 SEQID-02032 0.01 0.05 0.03 0.05 0.03 0.01 0.020.08 −19.30 0.61 0.00 7.53 0.23 0.33 0.00 0.00 SEQID-02033 0.02 0.080.05 0.05 0.05 0.02 0.03 0.08 −18.53 0.45 0.00 6.31 0.22 0.33 0.00 0.22SEQID-02034 0.03 0.03 0.04 0.03 0.03 0.02 0.04 0.07 −22.24 0.40 0.018.52 0.20 0.34 0.00 0.21 SEQID-02035 0.04 0.05 0.03 0.06 0.06 0.00 0.090.04 −17.35 0.41 0.05 9.69 0.26 0.30 0.00 0.23 SEQID-02036 0.06 0.050.11 0.05 0.07 0.00 0.02 0.04 −22.02 0.20 0.06 10.52 0.28 0.37 0.27 0.26SEQID-02037 0.03 0.04 0.03 0.06 0.06 0.01 0.02 0.08 −20.95 0.45 0.029.48 0.21 0.33 0.00 0.24 SEQID-02038 0.01 0.02 0.03 0.04 0.05 0.03 0.090.09 −23.12 0.36 0.06 10.69 0.00 0.30 0.23 0.21 SEQID-02039 0.03 0.020.02 0.06 0.04 0.01 0.01 0.04 −23.29 0.20 −0.03 4.72 0.25 0.33 0.00 0.00SEQID-02040 0.00 0.08 0.06 0.06 0.07 0.00 0.05 0.06 −18.92 0.43 −0.034.56 0.21 0.31 0.21 0.21 SEQID-02041 0.04 0.02 0.03 0.03 0.03 0.02 0.070.05 −25.62 0.42 −0.06 4.47 0.21 0.32 0.22 0.18 SEQID-02042 0.02 0.060.02 0.04 0.07 0.01 0.02 0.07 −20.68 0.45 −0.03 4.97 0.00 0.33 0.00 0.19SEQID-02043 0.06 0.03 0.03 0.06 0.04 0.00 0.00 0.06 −25.21 0.43 −0.074.34 0.25 0.34 0.23 0.00 SEQID-02044 0.06 0.05 0.10 0.07 0.06 0.00 0.020.03 −22.27 0.22 0.07 10.62 0.25 0.37 0.26 0.27 SEQID-02045 0.05 0.040.02 0.05 0.04 0.00 0.02 0.08 −19.54 0.57 0.00 6.55 0.23 0.32 0.00 0.24SEQID-02046 0.03 0.04 0.04 0.06 0.06 0.00 0.02 0.07 −24.59 0.32 −0.114.15 0.22 0.35 0.00 0.00 SEQID-02047 0.03 0.04 0.04 0.05 0.04 0.01 0.040.09 −18.87 0.49 −0.02 4.99 0.21 0.34 0.20 0.22 SEQID-02048 0.03 0.040.05 0.03 0.05 0.00 0.03 0.06 −25.99 0.25 −0.11 4.09 0.22 0.36 0.00 0.22SEQID-02049 0.03 0.06 0.07 0.06 0.05 0.03 0.04 0.06 −19.40 0.39 −0.044.55 0.21 0.33 0.00 0.23 SEQID-02050 0.00 0.10 0.02 0.06 0.05 0.01 0.040.07 −22.40 0.42 −0.19 3.30 0.16 0.41 0.18 0.19 SEQID-02051 0.01 0.030.01 0.05 0.05 0.00 0.04 0.08 −24.36 0.33 0.09 11.10 0.23 0.29 0.26 0.00SEQID-02052 0.04 0.03 0.04 0.04 0.04 0.02 0.05 0.05 −22.91 0.49 −0.034.73 0.21 0.32 0.00 0.23 SEQID-02053 0.02 0.04 0.05 0.09 0.05 0.01 0.020.05 −22.60 0.23 0.02 9.77 0.25 0.32 0.00 0.25 SEQID-02054 0.03 0.080.05 0.06 0.05 0.05 0.03 0.04 −16.03 0.28 −0.03 5.51 0.40 0.48 0.00 0.24SEQID-02055 0.04 0.05 0.04 0.04 0.04 0.02 0.05 0.06 −21.40 0.40 0.018.44 0.20 0.33 0.00 0.00 SEQID-02056 0.03 0.14 0.04 0.04 0.05 0.07 0.030.06 −11.96 0.78 −0.01 5.83 0.20 0.32 0.00 0.23 SEQID-02057 0.05 0.050.04 0.02 0.02 0.04 0.07 0.07 −21.18 0.39 −0.03 5.20 0.21 0.31 0.00 0.20SEQID-02058 0.03 0.04 0.07 0.05 0.06 0.02 0.03 0.09 −15.02 0.54 −0.025.10 0.29 0.45 0.00 0.23 SEQID-02059 0.04 0.07 0.05 0.05 0.04 0.02 0.040.08 −10.95 1.04 0.03 10.49 0.21 0.34 0.00 0.21 SEQID-02060 0.02 0.010.01 0.06 0.07 0.01 0.02 0.06 −22.39 0.18 −0.02 5.77 0.23 0.36 0.18 0.21SEQID-02061 0.01 0.04 0.05 0.04 0.05 0.01 0.02 0.06 −20.56 0.42 −0.024.99 0.20 0.33 0.21 0.21 SEQID-02062 0.04 0.05 0.05 0.04 0.04 0.01 0.020.08 −20.85 0.52 −0.02 4.76 0.21 0.36 0.20 0.22 SEQID-02063 0.02 0.070.05 0.04 0.05 0.01 0.06 0.04 −19.08 0.36 0.00 6.75 0.20 0.35 0.00 0.21SEQID-02064 0.03 0.05 0.05 0.04 0.06 0.02 0.04 0.07 −18.79 0.44 −0.044.64 0.19 0.34 0.00 0.21 SEQID-02065 0.04 0.06 0.05 0.04 0.05 0.01 0.050.06 −18.55 0.48 −0.02 5.32 0.19 0.35 0.00 0.20 SEQID-02066 0.03 0.050.04 0.05 0.05 0.03 0.05 0.06 −18.95 0.40 −0.01 6.14 0.18 0.35 0.20 0.19SEQID-02067 0.02 0.01 0.04 0.06 0.04 0.00 0.05 0.12 −22.91 0.61 −0.024.88 0.25 0.32 0.25 0.00 SEQID-02068 0.08 0.07 0.07 0.09 0.05 0.00 0.030.02 −26.12 0.09 0.07 10.60 0.24 0.31 0.17 0.00 SEQID-02069 0.04 0.040.04 0.03 0.05 0.02 0.04 0.11 −17.36 0.62 −0.01 5.87 0.25 0.30 0.00 0.26SEQID-02070 0.01 0.03 0.03 0.03 0.08 0.00 0.04 0.08 −23.78 0.34 0.029.75 0.25 0.34 0.27 0.23 SEQID-02071 0.03 0.06 0.04 0.05 0.04 0.04 0.050.03 −17.18 0.59 0.00 6.52 0.21 0.34 0.24 0.00 SEQID-02072 0.03 0.060.04 0.05 0.03 0.04 0.05 0.04 −17.10 0.62 0.00 6.52 0.21 0.34 0.24 0.00SEQID-02073 0.01 0.05 0.10 0.03 0.06 0.01 0.05 0.07 −18.26 0.47 0.039.73 0.25 0.31 0.00 0.24 SEQID-02074 0.04 0.04 0.03 0.08 0.06 0.01 0.050.08 −14.10 0.64 −0.02 4.89 0.28 0.34 0.00 0.00 SEQID-02075 0.03 0.050.06 0.03 0.03 0.01 0.07 0.06 −24.22 0.34 0.00 6.97 0.22 0.31 0.00 0.23SEQID-02076 0.02 0.04 0.06 0.06 0.07 0.03 0.05 0.07 −20.99 0.36 −0.034.68 0.42 0.53 0.00 0.24 SEQID-02077 0.03 0.03 0.05 0.04 0.09 0.00 0.0

4 0.07 −19.18 0.30 0.08 10.75 0.22 0.32 0.18 0.26 SEQID-02078 0.03 0.040.06 0.05 0.03 0.03 0.02 0.09 −17.54 0.60 −0.02 5.90 0.17 0.34 0.00 0.19SEQID-02079 0.01 0.05 0.05 0.06 0.06 0.02 0.10 0.03 −13.17 0.30 −0.024.59 0.22 0.32 0.00 0.23 SEQID-02080 0.02 0.11 0.03 0.04 0.04 0.03 0.060.04 −23.47 0.37 0.00 6.91 0.20 0.32 0.00 0.20 SEQID-02081 0.04 0.050.06 0.04 0.05 0.01 0.06 0.05 −20.97 0.33 0.00 6.80 0.21 0.33 0.00 0.00SEQID-02082 0.04 0.07 0.05 0.04 0.06 0.01 0.0

0.07 −16.07 0.50 −0.02 5.43 0.22 0.33 0.00 0.

2 SEQID-02083 0.03 0.05 0.04 0.04 0.05 0.02 0.06 0.06 −18.69 0.44 −0.024.94 0.21 0.34 0.21 0.21 SEQID-02084 0.06 0.07 0.05 0.04 0.06 0.05 0.080.05 −17.64 0.40 −0.02 5.65 0.20 0.31 0.00 0.21 SEQID-02085 0.00 0.030.03 0.05 0.04 0.02 0.08 0.03 −18.57 0.29 −0.04 4.95 0.21 0.33 0.22 0.22SEQID-02086 0.04 0.06 0.05 0.04 0.07 0.02 0.05 0.05 −16.31 0.46 −0.025.48 0.20 0.33 0.00 0.21 SEQID-02087 0.03 0.04 0.03 0.03 0.04 0.01 0.050.07 −23.59 0.37 −0.03 4.89 0.19 0.33 0.00 0.20 SEQID-02088 0.00 0.100.03 0.06 0.05 0.01 0.04 0.08 −20.74 0.42 −0.17 3.39 0.15 0.41 0.19 0.19SEQID-02089 0.02 0.00 0.01 0.09 0.03 0.02 0.04 0.18 −17.01 0.91 −0.044.37 0.33 0.29 0.00 0.27 SEQID-02090 0.01 0.09 0.05 0.04 0.10 0.04 0.050.03 −16.04 0.63 −0.01 5.76 0.26 0.27 0.00 0.23 SEQID-02091 0.02 0.030.06 0.06 0.05 0.00 0.05 0.05 −24.85 0.21 0.08 10.85 0.25 0.30 0.00 0.00SEQID-02092 0.02 0.07 0.07 0.01 0.07 0.00 0.03 0.11 −24.25 0.43 0.0610.72 0.29 0.32 0.00 0.25 SEQID-02093 0.04 0.00 0.02 0.03 0.07 0.00 0.050.07 −26.07 0.29 0.14 11.85 0.2

0.29 0.28 0.00 SEQID-02094 0.02 0.06 0.02 0.04 0.09 0.00 0.08 0.08−20.86 0.38 −0.04 4.59 0.25 0.34 0.25 0.22 SEQID-02095 0.03 0.07 0.040.05 0.03 0.04 0.01 0.06 −20.82 0.50 −0.01 6.27 0.25 0.30 0.23 0.22SEQID-02096 0.01 0.02 0.03 0.03 0.08 0.00 0.10 0.07 −19.24 0.42 −0.044.45 0.00 0.31 0.00 0.24 SEQID-02097 0.01 0.01 0.04 0.04 0.04 0.01 0.010.13 −19.37 0.48 0.10 11.46 0.00 0.34 0.00 0.23 SEQID-02098 0.02 0.040.05 0.09 0.07 0.01 0.02 0.04 −21.54 0.21 0.03 9.97 0.25 0.33 0.00 0.23SEQID-02099 0.06 0.05 0.04 0.04 0.05 0.00 0.04 0.06 −20.26 0.40 0.039.94 0.00 0.30 0.00 0.22 SEQID-02100 0.04 0.04 0.03 0.07 0.05 0.01 0.050.05 −23.47 0.38 −0.04 4.61 0.23 0.33 0.00 0.00 SEQID-02101 0.03 0.020.04 0.04 0.05 0.00 0.06 0.07 −21.34 0.25 0.01 8.71 0.21 0.31 0.00 0.25SEQID-02102 0.02 0.04 0.02 0.04 0.07 0.02 0.08 0.06 −23.24 0.21 −0.036.18 0.22 0.29 0.21 0.22 SEQID-02103 0.04 0.03 0.04 0.04 0.06 0.01 0.030.07 −21.63 0.38 0.01 8.67 0.20 0.31 0.19 0.00 SEQID-02104 0.05 0.040.08 0.05 0.08 0.01 0.05 0.05 −17.60 0.49 0.00 7.29 0.21 0.30 0.23 0.19SEQID-02105 0.02 0.06 0.04 0.04 0.06 0.03 0.04 0.06 −21.56 0.46 0.049.87 0.25 0.36 0.00 0.00 SEQID-02106 0.03 0.08 0.05 0.04 0.03 0.01 0.040.06 −17.76 0.58 0.01 8.77 0.22 0.35 0.00 0.20 SEQID-02107 0.03 0.060.04 0.04 0.05 0.02 0.06 0.0

−19.10 0.39 −0.01 6.27 0.21 0.33 0.00 0.19 SEQID-02108 0.03 0.04 0.030.05 0.06 0.02 0.03 0.05 −19.58 0.47 −0.04 4.60 0.51 0.68 0.21 0.21SEQID-02109 0.02 0.02 0.04 0.03 0.06 0.02 0.05 0.08 −20.33 0.44 −0.025.35 0.21 0.35 0.00 0.22 SEQID-02110 0.04 0.07 0.06 0.04 0.06 0.02 0.060.05 −19.17 0.36 −0.04 4.63 0.21 0.33 0.20 0.22 SEQID-02111 0.03 0.070.02 0.06 0.05 0.02 0.02 0.08 −11.09 1.13 −0.01 4.93 0.20 0.32 0.00 0.22SEQID-02112 0.04 0.05 0.05 0.04 0.04 0.00 0.04 0.08 −22.16 0.40 −0.044.71 0.21 0.32 0.00 0.22 SEQID-02113 0.03 0.03 0.06 0.04 0.05 0.30 0.0

0.08 −20.86 0.51 −0.03 4.69 0.19 0.34 0.00 0.22 SEQID-02114 0.02 0.030.06 0.05 0.06 0.03 0.04 0.08 −16.41 0.40 −0.01 5.65 0.20 0.39 0.00 0.21SEQID-02115 0.04 0.05 0.06 0.04 0.06 0.01 0.03 0.06 −18.27 0.45 −0.034.75 0.18 0.33 0.00 0.22 SEQID-02116 0.01 0.04 0.04 0.04 0.03 0.04 0.040.08 −20.93 0.45 −0.02 5.70 0.18 0.37 0.19 0.20 SEQID-02117 0.05 0.060.04 0.01 0.10 0.02 0.04 0.08 −19.43 0.36 0.13 11.09 0.26 0.22 0.19 0.25SEQID-02118 0.01 0.04 0.06 0.04 0.08 0.00 0.00 0.10 −26.77 0.32 0.0410.37 0.25 0.29 0.00 0.28 SEQID-02119 0.04 0.03 0.03 0.08 0.05 0.00 0.060.15 −17.89 0.60 −0.01 5.70 0.21 0.30 0.00 0.00 SEQID-02120 0.04 0.050.02 0.06 0.05 0.02 0.06 0.05 −24.70 0.24 −0.02 4.91 0.26 0.30 0.29 0.27SEQID-02121 0.03 0.02 0.04 0.03 0.06 0.00 0.03 0.09 −24.80 0.40 0.039.83 0.23 0.29 0.23 0.00 SEQID-02122 0.04 0.13 0.04 0.04 0.04 0.04 0.010.04 −8.41 1.32 0.01 8.53 0.19 0.28 0.21 0.00 SEQID-02123 0.03 0.04 0.050.08 0.06 0.00 0.06 0.08 −17.19 0.53 0.04 10.00 0.26 0.31 0.24 0.25SEQID-02124 0.02 0.03 0.04 0.08 0.05 0.00 0.02 0.04 −18.96 0.32 0.1111.71 0.25 0.31 0.26 0.26 SEQID-02125 0.03 0.03 0.01 0.05 0.02 0.00 0.040.02 −21.54 0.50 −0.02 4.88 0.24 0.36 0.25 0.25 SEQID-02126 0.01 0.090.02 0.03 0.06 0.03 0.03 0.0

−20.43 0.65 −0.04 4.40 0.00 0.32 0.22 0.23 SEQID-02127 0.06 0.02 0.030.06 0.05 0.01 0.05 0.08 −24.19 0.25 0.10 11.65 0.22 0.31 0.00 0.22SEQID-02128 0.03 0.07 0.03 0.06 0.03 0.01 0.05 0.07 −18.79 0.54 0.006.77 0.24 0.30 0.00 0.23 SEQID-02129 0.01 0.03 0.00 0.04 0.02 0.00 0.020.04 −22.65 0.43 −0.03 4.83 0.27 0.35 0.00 0.21 SEQID-02130 0.03 0.050.03 0.04 0.06 0.01 0.03 0.09 −17.91 0.60 −0.01 5.86 0.30 0.35 0.22 0.20SEQID-02131 0.03 0.03 0.02 0.07 0.04 0.01 0.03 0.07 −22.77 0.31 −0.034.71 0.22 0.34 0.00 0.21 SEQID-02132 0.03 0.04 0.03 0.05 0.05 0.02 0.040.08 −20.20 0.48 −0.05 4.58 0.38 0.50 0.17 0.25 SEQID-02133 0.03 0.070.02 0.06 0.05 0.02 0.03 0.05 −23.22 0.29 −0.03 4.63 0.22 0.33 0.22 0.00SEQID-02134 0.02 0.06 0.02 0.04 0.06 0.00 0.04 0.05 −16.13 0.39 −0.123.40 0.26 0.39 0.33 0.26 SEQID-02135 0.04 0.01 0.04 0.05 0.04 0.00 0.040.09 −18.90 0.49 −0.01 6.38 0.22 0.31 0.21 0.22 SEQID-02136 0.05 0.040.03 0.05 0.05 0.01 0.03 0.06 −19.17 0.55 −0.03 5.05 0.22 0.33 0.00 0.00SEQID-02137 0.02 0.05 0.06 0.03 0.06 0.01 0.05 0.11 −15.26 0.59 −0.044.43 0.21 0.32 0.20 0.23 SEQID-02138 0.05 0.04 0.05 0.04 0.04 0.00 0.050.07 −18.34 0.47 −0.02 5.32 0.19 0.31 0.20 0.19 SEQID-02139 0.04 0.030.04 0.04 0.04 0.00 0.023 0.10 −17.78 0.55 −0.03 4.78 0.22 0.39 0.220.21 SEQID-02140 0.01 0.05 0.04 0.04 0.07 0.00 0.04 0.05 −21.80 0.900.00 6.75 0.22 0.34 0.00 0.23 SEQID-02141 0.04 0.03 0.04 0.04 0.04 0.010.07 0.08 −20.82 0.37 0.01 8.41 0.22 0.33 0.00 0.18 SEQID-02142 0.030.05 0.05 0.04 0.07 0.00 0.0

0.05 −17.71 0.43 −0.01 6.55 0.21 0.34 0.00 0.20 SEQID-02143 0.02 0.090.04 0.06 0.05 0.00 0.01 0.12 −11.90 1.31 −0.05 4.02 0.21 0.34 0.00 0.22SEQID-02144 0.032 0.04 0.03 0.04 0.06 0.01 0.03 0.09 −17.41 0.56 −0.025.83 0.21 0.34 0.00 0.22 SEQID-02145 0.03 0.02 0.04 0.04 0.04 0.00 0.030.09 −18.17 0.53 −0.03 5.38 0.22 0.33 0.00 0.22 SEQID-02146 0.02 0.060.04 0.03 0.04 0.03 0.05 0.08 −21.40 0.41 −0.01 6.68 0.20 0.31 0.00 0.21SEQID-02147 0.03 0.04 0.02 0.06 0.05 0.04 0.05 0.03 −22.57 0.18 −0.044.69 0.20 0.34 0.00 0.20 SEQID-02148 0.02 0.02 0.05 0.06 0.06 0.01 0.030.07 −22.27 0.37 −0.04 4.57 0.19 0.35 0.00 0.21 SEQID-02149 0.03 0.040.03 0.04 0.05 0.02 0.07 0.05 −21.30 0.34 −0.02 5.61 0.20 0.32 0.00 0.20SEQID-02150 0.10 0.03 0.02 0.14 0.04 0.02 0.08 0.08 −11.67 0.51 −0.034.42 0.21 0.43 0.19 0.

2 SEQID-02151 0.02 0.07 0.04 0.04 0.03 0.03 0.07 0.05 −21.86 0.34 −0.044.62 0.19 0.33 0.00 0.20 SEQID-02152 0.03 0.04 0.05 0.04 0.06 0.01 0.050.07 −19.74 0.46 −0.03 4.67 0.19 0.37 0.18 0.20 SEQID-02153 0.02 0.040.04 0.05 0.04 0.02 0.05 0.05 −20.57 0.34 −0.01 6.46 0.19 0.33 0.19 0.20SEQID-02154 0.02 0.05 0.03 0.06 0.05 0.00 0.03 0.06 −24.92 0.30 −0.173.61 0.20 0.35 0.20 0.21 SEQID-02155 0.01 0.06 0.05 0.04 0.05 0.03 0.060.05 −18.77 0.38 −0.02 5.27 0.18 0.37 0.19 0.19 SEQID-02156 0.04 0.090.06 0.04 0.11 0.03 0.05 0.02 −12.76 0.65 0.00 6.65 0.27 0.19 0.312 0.26SEQID-02157 0.02 0.00 0.04 0.04 0.04 0.00 0.00 0.01 −27.75 0.24 0.0410.19 0.34 0.30 0.27 0.30 SEQID-02158 0.05 0.05 0.05 0.01 0.04 0.02 0.020.04 −33.89 0.16 0.01 7.70 0.27 0.23 0.00 0.00 SEQID-02159 0.04 0.020.04 0.06 0.08 0.02 0.06 0.07 −17.85 0.43 −0.01 5.74 0.29 0.29 0.27 0.28SEQID-02160 0.02 0.05 0.02 0.04 0.02 0.02 0.08 0.14 −21.12 0.33 0.039.08 0.27 0.26 0.00 0.27 SEQID-02161 0.04 0.06 0.04 0.05 0.07 0.00 0.000.08 −20.90 0.46 0.01 8.23 0.27 0.30 0.00 0.23 SEQID-02162 0.09 0.050.03 0.08 0.05 0.00 0.07 0.06 −21.10 0.31 0.00 6.83 0.00 0.28 0.00 0.00SEQID-02163 0.07 0.08 0.09 0.10 0.04 0.00 0.01 0.02 −23.49 0.11 0.0710.67 0.27 0.39 0.22 0.27 SEQID-02164 0.03 0.05 0.03 0.04 0.03 0.02 0.040.10 −15.36 0.73 0.03 9.19 0.26 0.31 0.29 0.00 SEQID-02165 0.04 0.040.06 0.04 0.06 0.03 0.04 0.13 −16.83 0.54 −0.05 4.24 0.40 0.46 0.00 0.24SEQID-02166 0.02 0.02 0.05 0.04 0.08 0.00 0.03 0.04 −25.16 0.37 0.0710.46 0.27 0.28 0.00 0.00 SEQID-02167 0.04 0.02 0.04 0.05 0.05 0.00 0.040.13 −25.40 0.28 0.12 11.02 0.23 0.29 0.22 0.00 SEQID-02168 0.05 0.030.03 0.03 0.03 0.00 0.03 0.06 −22.21 0.32 −0.05 4.38 0.24 0.32 0.28 0.24SEQID-02169 0.03 0.08 0.06 0.03 0.07 0.01 0.05 0.12 −16.54 0.74 −0.015.19 0.23 0.32 0.00 0.21 SEQID-02170 0.04 0.02 0.03 0.04 0.10 0.01 0.030.07 −20.64 0.43 0.09 11.06 0.24 0.30 0.00 0.23 SEQID-02171 0.03 0.030.03 0.02 0.05 0.00 0.04 0.10 −23.32 0.33 0.10 11.21 0.20 0.29 0.24 0.00SEQID-02172 0.02 0.05 0.05 0.02 0.06 0.03 0.06 0.06 −17.37 0.50 0.006.52 0.31 0.31 0.21 0.22 SEQID-02173 0.03 0.04 0.03 0.04 0.08 0.01 0.020.08 −18.83 0.69 −0.04 4.48 0.00 0.33 0.00 0.21 SEQID-02174 0.01 0.070.05 0.04 0.06 0.01 0.06 0.07 −16.84 0.65 −0.03 4.65 0.33 0.31 0.00 0.

4 SEQID-02175 0.06 0.09 0.03 0.07 0.06 0.01 0.02 0.12 −9.86 1.25 −0.034.30 0.20 0.31 0.00 0.22 SEQID-02176 0.02 0.03 0.05 0.05 0.04 0.02 0.020.08 −19.08 0.45 −0.06 4.48 0.00 0.33 0.00 0.23 SEQID-02177 0.03 0.060.06 0.04 0.06 0.02 0.10 0.06 −16.64 0.38 −0.01 6.12 0.22 0.30 0.22 0.00SEQID-02178 0.06 0.09 0.04 0.06 0.07 0.05 0.06 0.09 −12.20 0.88 0.029.25 0.21 0.29 0.00 0.19 SEQID-02179 0.02 0.04 0.05 0.05 0.06 0.02 0.030.08 −15.62 0.57 −0.02 5.15 0.20 0.32 0.00 0.24 SEQID-02180 0.04 0.030.05 0.05 0.06 0.01 0.03 0.10 −15.23 0.64 −0.02 4.99 0.27 0.38 0.00 0.00SEQID-02181 0.05 0.03 0.03 0.05 0.05 0.01 0.03 0.07 −20.34 0.42 −0.015.12 0.24 0.34 0.00 0.19 SEQID-02182 0.02 0.07 0.04 0.03 0.05 0.02 0.060.07 −21.19 0.43 −0.02 5.47 0.22 0.31 0.00 0.00 SEQID-02183 0.03 0.030.06 0.04 0.05 0.03 0.05 0.06 −16.88 0.56 −0.01 6.36 0.20 0.31 0.00 0.00SEQID-02184 0.02 0.03 0.03 0.05 0.06 0.01 0.03 0.06 −22.05 0.41 −0.044.61 0.24 0.31 0.00 0.00 SEQID-02185 0.03 0.05 0.05 0.03 0.05 0.01 0.070.06 −20.27 0.37 −0.01 6.51 0.21 0.34 0.00 0.00 SEQID-02186 0.02 0.110.04 0.02 0.05 0.04 0.06 0.07 −11.45 0.82 −0.01 6.51 0.22 0.31 0.00 0.21SEQID-02187 0.02 0.06 0.05 0.08 0.06 0.07 0.04 0.05 −18.36 0.40 −0.044.52 0.19 0.34 0.00 0.21 SEQID-02188 0.05 0.08 0.03 0.04 0.04 0.01 0.060.07 −22.44 0.39 −0.04 4.83 0.20 0.32 0.17 0.20 SEQID-02189 0.04 0.050.05 0.03 0.05 0.02 0.03 0.06 −18.28 0.54 −0.01 6.44 0.17 0.31 0.23 0.21SEQID-02190 0.04 0.03 0.05 0.04 0.06 0.01 0.03 0.08 −15.62 0.60 0.005.94 0.22 0.38 0.00 0.24 SEQID-02191 0.03 0.06 0.03 0.06 0.06 0.01 0.030.05 −16.55 0.51 −0.02 5.25 0.23 0.32 0.23 0.21 SEQID-02192 0.04 0.030.07 0.05 0.09 0.01 0.04 0.09 −14.81 0.52 −0.01 5.23 0.21 0.38 0.18 0.21SEQID-02193 0.03 0.06 0.06 0.05 0.03 0.04 0.05 0.07 −10.43 1.03 −0.014.79 0.22 0.34 0.00 0.23 SEQID-02194 0.01 0.07 0.03 0.04 0.06 0.01 0.020.08 −15.31 0.79 −0.03 4.51 0.23 0.33 0.23 0.22 SEQID-02195 0.02 0.050.08 0.03 0.06 0.05 0.04 0.05 −19.05 0.33 −0.02 4.95 0.22 0.38 0.21 0.22SEQID-02196 0.03 0.09 0.05 0.05 0.05 0.05 0.03 0.03 −10.73 0.96 −0.025.16 0.21 0.32 0.00 0.22 SEQID-02197 0.00 0.02 0.10 0.07 0.10 0.02 0.000.08 −26.49 0.28 −0.14 3.92 0.21 0.43 0.21 0.23 SEQID-02198 0.01 0.090.10 0.06 0.06 0.01 0.02 0.10 −13.64 0.45 −0.08 3.66 0.26 0.35 0.21 0.24SEQID-02199 0.02 0.04 0.04 0.04 0.04 0.02 0.05 0.05 −18.85 0.42 −0.025.50 0.20 0.31 0.00 0.21 SEQID-02200 0.03 0.04 0.05 0.06 0.07 0.02 0.050.05 −18.13 0.35 −0.03 4.90 0.22 0.33 0.00 0.21 SEQID-02201 0.04 0.040.05 0.04 0.04 0.02 0.05 0.07 −17.57 0.46 −0.02 5.62 0.21 0.32 0.20 0.21SEQID-02202 0.03 0.04 0.05 0.04 0.06 0.05 0.05 0.06 −20.49 0.35 −0.025.54 0.00 0.32 0.00 0.22 SEQID-02203 0.02 0.05 0.05 0.04 0.05 0.01 0.060.05 −21.67 0.31 −0.01 6.52 0.18 0.32 0.00 0.21 SEQID-02204 0.02 0.060.03 0.05 0.07 0.01 0.05 0.05 −23.34 0.33 −0.04 4.74 0.25 0.40 0.00 0.20SEQID-02205 0.03 0.05 0.05 0.04 0.05 0.03 0.04 0.06 −20.67 0.33 −0.034.77 0.42 0.71 0.00 0.21 SEQID-02206 0.02 0.05 0.04 0.05 0.05 0.03 0.030.07 −15.97 0.76 −0.02 4.80 0.19 0.34 0.18 0.20 SEQID-02207 0.02 0.030.06 0.04 0.07 0.03 0.04 0.08 −23.26 0.31 −0.01 5.64 0.00 0.35 0.00 0.00SEQID-02208 0.03 0.03 0.03 0.05 0.05 0.02 0.09 0.05 −23.56 0.26 0.049.73 0.00 0.35 0.00 0.17 SEQID-02209 0.03 0.03 0.01 0.04 0.04 0.01 0.030.04 −28.21 0.23 −0.02 5.45 0.19 0.56 0.19 0.00 SEQID-02210 0.03 0.040.02 0.04 0.04 0.01 0.03 0.04 −26.63 0.25 −0.01 5.91 0.20 0.53 0.19 0.18SEQID-02211 0.02 0.04 0.04 0.06 0.06 0.02 0.03 0.08 −24.06 0.30 −0.016.23 0.00 0.38 0.00 0.00 SEQID-02212 0.04 0.04 0.02 0.03 0.05 0.01 0.030.05 −26.31 0.29 −0.02 5.33 0.26 0.54 0.18 0.18 SEQID-02213 0.03 0.050.04 0.05 0.06 0.02 0.04 0.08 −19.00 0.62 −0.03 4.86 0.19 0.35 0.00 0.20SEQID-02214 0.04 0.00 0.00 0.03 0.03 0.00 0.01 0.05 −32.13 0.13 −0.035.10 0.38 0.55 0.21 0.21 SEQID-02215 0.04 0.04 0.02 0.03 0.05 0.03 0.040.04 −23.77 0.30 −0.03 4.98 0.21 0.24 0.00 0.19 SEQID-02216 0.02 0.040.06 0.07 0.07 0.02 0.05 0.09 −19.87 0.35 0.01 8.15 0.18 0.38 0.19 0.21SEQID-02217 0.05 0.04 0.04 0.05 0.06 0.02 0.06 0.05 −19.66 0.42 −0.035.05 0.00 0.30 0.00 0.20 SEQID-02218 0.04 0.07 0.04 0.03 0.06 0.01 0.060.05 −20.75 0.42 −0.01 6.25 0.21 0.33 0.00 0.21 SEQID-02219 0.03 0.040.01 0.04 0.04 0.01 0.03 0.04 −27.49 0.25 −0.02 5.63 0.18 0.53 0.18 0.18SEQID-02220 0.04 0.04 0.01 0.04 0.04 0.01 0.03 0.04 −27.72 0.23 −0.025.64 0.19 0.51 0.18 0.18 SEQID-02221 0.05 0.06 0.04 0.04 0.07 0.01 0.060.06 −19.58 0.45 −0.01 6.33 0.21 0.34 0.21 0.19 SEQID-02222 0.03 0.040.01 0.04 0.04 0.01 0.03 0.03 −28.29 0.22 −0.02 5.42 0.19 0.49 0.18 0.18SEQID-02223 0.01 0.03 0.06 0.05 0.08 0.03 0.05 0.10 −20.80 0.34 0.007.29 0.19 0.32 0.18 0.21 SEQID-02224 0.02 0.05 0.06 0.06 0.06 0.03 0.060.07 −19.95 0.34 0.00 6.73 0.19 0.37 0.20 0.19 SEQID-02225 0.03 0.050.05 0.06 0.06 0.03 0.07 0.07 −20.00 0.32 −0.01 6.59 0.18 0.33 0.19 0.19SEQID-02226 0.03 0.05 0.04 0.04 0.04 0.02 0.03 0.06 −23.59 0.30 0.006.84 0.42 0.64 0.00 0.20 SEQID-02227 0.04 0.06 0.03 0.06 0.04 0.02 0.040.06 −21.10 0.46 −0.02 5.40 0.00 0.35 0.00 0.19 SEQID-02228 0.02 0.030.05 0.04 0.06 0.01 0.06 0.06 −18.44 0.42 0.02 8.30 0.20 0.30 0.00 0.21SEQID-02229 0.03 0.04 0.05 0.04 0.05 0.03 0.05 0.08 −24.61 0.31 −0.015.58 0.20 0.33 0.19 0.19 SEQID-02230 0.04 0.05 0.03 0.02 0.04 0.02 0.060.06 −22.56 0.34 0.00 7.09 0.20 0.33 0.00 0.20 SEQID-02231 0.04 0.050.03 0.05 0.05 0.02 0.05 0.09 −19.29 0.45 0.01 8.31 0.72 0.89 0.00 0.00SEQID-02232 0.04 0.06 0.04 0.05 0.04 0.02 0.04 0.06 −22.05 0.44 −0.044.80 0.00 0.41 0.00 0.18 SEQID-02233 0.04 0.07 0.04 0.04 0.04 0.01 0.070.05 −22.35 0.33 0.00 6.87 0.20 0.33 0.00 0.21 SEQID-02234 0.02 0.050.03 0.04 0.04 0.02 0.03 0.06 −22.15 0.37 0.00 6.79 0.94 0.99 0.21 0.22SEQID-02235 0.03 0.05 0.04 0.04 0.04 0.02 0.03 0.07 −22.81 0.33 0.006.74 0.44 0.65 0.00 0.00 SEQID-02236 0.02 0.05 0.04 0.05 0.06 0.03 0.050.10 −21.98 0.35 0.00 6.84 0.19 0.33 0.19 0.19 SEQID-02237 0.05 0.050.03 0.04 0.04 0.03 0.04 0.04 −22.90 0.32 0.05 9.86 0.00 0.29 0.00 0.24SEQID-02238 0.02 0.03 0.02 0.03 0.02 0.01 0.01 0.02 −40.08 0.09 0.0710.40 0.26 0.39 0.24 0.00 SEQID-02239 0.04 0.08 0.03 0.05 0.04 0.01 0.030.05 −24.45 0.38 −0.05 4.47 0.39 0.54 0.00 0.19 SEQID-02240 0.01 0.050.04 0.05 0.06 0.03 0.06 0.09 −21.66 0.35 −0.01 5.77 0.20 0.33 0.19 0.21SEQID-02241 0.05 0.06 0.03 0.04 0.04 0.00 0.04 0.06 −21.24 0.38 −0.074.39 0.27 0.38 0.00 0.24 SEQID-02242 0.04 0.06 0.08 0.06 0.05 0.01 0.030.05 −20.78 0.20 0.01 7.73 0.24 0.39 0.22 0.26 SEQID-02243 0.04 0.030.01 0.08 0.05 0.00 0.04 0.03 −25.45 0.16 −0.03 5.11 0.31 0.49 0.00 0.21SEQID-02244 0.02 0.02 0.16 0.04 0.04 0.01 0.02 0.03 −14.16 0.16 0.029.58 0.57 0.83 0.21 0.38 SEQID-02245 0.05 0.06 0.08 0.03 0.02 0.00 0.030.06 −21.06 0.37 −0.05 4.40 0.26 0.35 0.00 0.24 SEQID-02246 0.04 0.030.07 0.07 0.07 0.02 0.03 0.05 −17.43 0.28 0.02 9.52 0.22 0.32 0.22 0.21SEQID-02247 0.05 0.05 0.03 0.04 0.07 0.02 0.03 0.07 −18.04 0.51 0.018.27 0.20 0.34 0.00 0.21 SEQID-02248 0.03 0.03 0.18 0.03 0.04 0.01 0.010.03 −15.17 0.17 −0.01 5.18 0.54 0.80 0.21 0.38 SEQID-02249 0.02 0.030.18 0.05 0.04 0.01 0.02 0.03 −14.55 0.17 −0.01 6.05 0.59 0.80 0.21 0.38SEQID-02250 0.02 0.04 0.04 0.05 0.05 0.02 0.04 0.06 −22.44 0.34 −0.015.99 0.21 0.50 0.19 0.21 SEQID-02251 0.05 0.02 0.03 0.06 0.04 0.03 0.020.12 −18.26 0.58 0.01 7.70 0.24 0.34 0.00 0.20 SEQID-02252 0.01 0.040.09 0.04 0.06 0.02 0.03 0.07 −23.00 0.39 0.00 5.90 0.21 0.41 0.21 0.22SEQID-02253 0.04 0.04 0.03 0.04 0.06 0.01 0.03 0.08 −21.44 0.45 0.017.94 0.21 0.33 0.00 0.21 SEQID-02254 0.05 0.01 0.03 0.04 0.03 0.02 0.020.06 −29.51 0.27 0.05 10.02 0.28 0.36 0.23 0.18 SEQID-02255 0.03 0.050.04 0.06 0.07 0.03 0.04 0.04 −23.64 0.19 0.02 9.54 0.22 0.31 0.00 0.22SEQID-02256 0.03 0.07 0.04 0.05 0.05 0.01 0.05 0.06 −19.33 0.42 −0.016.21 0.22 0.34 0.00 0.22 SEQID-02257 0.02 0.05 0.03 0.04 0.04 0.03 0.020.10 −20.08 0.43 0.00 7.41 0.67 0.84 0.00 0.00 SEQID-02258 0.03 0.020.04 0.06 0.0

0.00 0.01 0.08 −27.31 0.16 0.01 8.77 0.23 0.32 0.00 0.19 SEQID-022590.02 0.07 0.04 0.03 0.01 0.03 0.04 0.06 −34.51 0.37 −0.27 3.56 0.21 0.320.21 0.22 SEQID-02260 0.02 0.03 0.03 0.05 0.03 0.00 0.06 0.08 −25.520.42 0.01 8.15 0.24 0.30 0.00 0.22 SEQID-02261 0.04 0.03 0.05 0.03 0.040.05 0.03 0.05 −22.63 0.32 0.03 9.34 0.20 0.30 0.19 0.00 SEQID-022620.04 0.10 0.03 0.03 0.05 0.03 0.06 0.05 −17.15 0.58 0.06 10.27 0.23 0.340.22 0.00 SEQID-02263 0.03 0.05 0.01 0.05 0.04 0.02 0.04 0.05 −21.130.35 0.02 8.10 0.21 0.33 0.00 0.21 SEQID-02264 0.08 0.08 0.01 0.04 0.040.00 0.02 0.03 −30.26 0.28 −0.19 3.71 0.36 0.48 0.22 0.23 SEQID-022650.03 0.07 0.01 0.04 0.06 0.01 0.05 0.05 −23.75 0.45 −0.01 5.76 0.20 0.310.21 0.20 SEQID-02266 0.03 0.04 0.05 0.04 0.06 0.02 0.04 0.089 −20.890.41 0.03 9.59 0.21 0.31 0.00 0.22 SEQID-02267 0.01 0.04 0.06 0.07 0.080.03 0.05 0.09 −19.83 0.34 −0.01 5.53 0.20 0.34 0.19 0.21 SEQID-022680.03 0.08 0.03 0.06 0.05 0.04 0.07 0.07 −16.17 0.70 0.02 9.14 0.20 0.330.00 0.20 SEQID-02269 0.03 0.05 0.05 0.05 0.05 0.03 0.06 0.07 −19.200.36 0.00 6.73 0.19 0.32 0.19 0.19 SEQID-02270 0.02 0.05 0.07 0.05 0.070.01 0.05 0.09 −19.23 0.30 −0.01 6.31 0.00 0.37 0.17 0.21 SEQID-022710.03 0.03 0.03 0.07 0.05 0.02 0.02 0.05 −23.98 0.25 −0.05 4.70 0.00 0.360.00 0.00 SEQID-02272 0.05 0.05 0.04 0.05 0.06 0.02 0.06 0.05 −19.530.43 −0.03 5.15 0.21 0.31 0.00 0.22 SEQID-02273 0.03 0.06 0.03 0.03 0.040.02 0.06 0.06 −22.21 0.34 0.00 7.11 0.19 0.33 0.00 0.20 SEQID-022740.01 0.07 0.04 0.04 0.05 0.01 0.05 0.05 −25.20 0.34 −0.02 6.06 0.92 0.980.21 0.21 SEQID-02275 0.03 0.09 0.02 0.04 0.04 0.03 0.06 0.07 −16.860.55 0.07 10.36 0.20 0.34 0.00 0.00 SEQID-02276 0.04 0.06 0.03 0.04 0.060.02 0.04 0.09 −17.85 0.47 0.02 8.58 0.69 0.85 0.00 0.22 SEQID-022770.01 0.07 0.03 0.04 0.05 0.02 0.07 0.06 −21.18 0.25 0.07 8.51 0.21 0.320.21 0.23 SEQID-02278 0.04 0.08 0.06 0.05 0.03 0.02 0.08 0.07 −16.150.52 0.05 9.72 0.20 0.34 0.00 0.21 SEQID-02279 0.05 0.09 0.03 0.02 0.050.01 0.03 0.05 −24.33 0.31 −0.04 4.60 0.40 0.60 0.00 0.19 SEQID-022800.01 0.04 0.04 0.02 0.05 0.01 0.04 0.09 −20.24 0.49 0.00 7.29 0.19 0.330.24 0.23 SEQID-02281 0.05 0.08 0.05 0.02 0.06 0.00 0.01 0.03 −28.130.33 −0.05 4.67 0.22 0.26 0.00 0.21 SEQID-02282 0.02 0.00 0.00 0.04 0.020.00 0.03 0.03 −36.76 0.12 −0.09 4.39 0.58 0.69 0.22 0.22 SEQID-022830.05 0.03 0.02 0.03 0.04 0.00 0.01 0.09 −19.35 0.71 0.00 7.52 0.24 0.320.00 0.25 SEQID-02284 0.07 0.08 0.06 0.05 0.06 0.00 0.01 0.03 −24.420.31 −0.02 5.21 0.19 0.28 0.00 0.00 SEQID-02285 0.07 0.08 0.06 0.05 0.060.00 0.01 0.08 −24.41 0.32 −0.02 5.22 0.25 0.30 0.00 0.00 SEQID-022860.04 0.06 0.04 0.03 0.02 0.00 0.07 0.06 −21.17 0.39 −0.03 5.14 0.90 0.910.00 0.23 SEQID-02287 0.02 0.07 0.04 0.07 0.06 0.01 0.03 0.08 −16.530.44 0.03 9.09 0.25 0.33 0.22 0.26 SEQID-02288 0.02 0.08 0.02 0.02 0.030.02 0.02 0.11 −19.85 0.47 0.01 7.35 0.27 0.30 0.25 0.25 SEQID-022890.01 0.04 0.06 0.02 0.10 0.00 0.01 0.09 −14.29 0.62 0.00 7.39 0.59 0.650.24 0.25 SEQID-02290 0.05 0.11 0.04 0.02 0.05 0.00 0.02 0.05 −25.980.30 −0.05 4.56 0.41 0.59 0.23 0.00 SEQID-02291 0.01 0.07 0.01 0.05 0.030.02 0.06 0.09 −17.65 0.90 0.05 9.78 0.18 0.31 0.19 0.22 SEQID-022920.00 0.03 0.00 0.04 0.07 0.04 0.00 0.07 −21.86 0.40 −0.05 4.76 0.33 0.160.33 0.33 SEQID-02293 0.00 0.06 0.06 0.11 0.04 0.02 0.04 0.09 −19.050.25 0.05 10.11 0.27 0.23 0.25 0.24 SEQID-02294 0.06 0.06 0.02 0.02 0.050.00 0.04 0.09 −23.42 0.39 −0.08 4.32 0.38 0.46 0.25 0.00 SEQID-022950.04 0.03 0.03 0.04 0.07 0.00 0.05 0.08 −24.69 0.33 0.01 8.63 0.00 0.330.00 0.23 SEQID-02296 0.05 0.08 0.04 0.05 0.08 0.01 0.06 0.07 −14.960.61 0.05 10.35 0.21 0.33 0.00 0.24 SEQID-02297 0.02 0.05 0.03 0.04 0.060.01 0.03 0.06 −22.33 0.36 −0.01 5.96 0.71 0.89 0.00 0.21 SEQID-022980.01 0.04 0.04 0.04 0.05 0.00 0.03 0.03 −23.86 0.30 0.14 11.71 0.24 0.300.00 0.21 SEQID-02299 0.03 0.04 0.04 0.04 0.04 0.01 0.01 0.10 −20.100.57 0.00 6.92 0.21 0.34 0.21 0.22 SEQID-02300 0.03 0.06 0.04 0.05 0.030.02 0.07 0.04 −20.39 0.35 0.02 8.61 0.19 0.32 0.22 0.21 SEQID-023010.05 0.08 0.03 0.03 0.04 0.06 0.04 0.03 −20.36 0.39 −0.02 6.09 0.51 0.630.25 0.25 SEQID-02302 0.03 0.10 0.05 0.03 0.04 0.03 0.06 0.06 −17.770.42 0.02 8.21 0.00 0.31 0.00 0.24 SEQID-02303 0.01 0.10 0.08 0.07 0.040.02 0.02 0.05 −23.34 0.27 0.01 7.38 0.25 0.35 0.23 0.23 SEQID-023040.09 0.04 0.05 0.07 0.07 0.04 0.06 0.05 −14.98 0.69 −0.05 4.44 0.21 0.310.00 0.19 SEQID-02305 0.03 0.03 0.02 0.06 0.04 0.01 0.06 0.04 −25.770.30 −0.05 4.48 0.24 0.33 0.00 0.23 SEQID-02306 0.03 0.07 0.02 0.07 0.050.02 0.04 0.05 −18.34 0.62 0.02 9.36 0.18 0.35 0.19 0.20 SEQID-023070.02 0.04 0.06 0.08 0.05 0.02 0.03 0.07 −17.22 0.57 −0.01 6.46 0.00 0.390.16 0.19 SEQID-02308 0.01 0.03 0.04 0.05 0.06 0.01 0.05 0.06 −18.980.41 0.00 6.89 0.22 0.33 0.00 0.20 SEQID-02309 0.03 0.05 0.04 0.09 0.060.03 0.03 0.05 −18.07 0.40 −0.01 6.18 0.38 0.61 0.18 0.21 SEQID-023100.05 0.07 0.05 0.03 0.04 0.02 0.04 0.07 −22.73 0.36 −0.04 4.83 0.21 0.350.00 0.22 SEQID-02311 0.02 0.06 0.04 0.05 0.04 0.02 0.03 0.06 −20.550.57 0.00 6.88 0.21 0.33 0.00 0.22 SEQID-02312 0.01 0.05 0.03 0.05 0.040.03 0.04 0.11 −24.64 0.30 −0.02 5.77 0.38 0.44 0.00 1.00 SEQID-023130.03 0.06 0.05 0.05 0.05 0.03 0.05 0.05 −23.03 0.33 −0.01 6.04 0.23 0.300.00 0.20 SEQID-02314 0.03 0.06 0.05 0.05 0.05 0.03 0.04 0.08 −17.360.45 −0.02 5.73 0.18 0.33 0.00 0.21 SEQID-02315 0.01 0.06 0.06 0.06 0.060.04 0.08 0.04 −12.07 0.45 0.01 7.96 1.00 1.00 0.22 0.22 SEQID-023160.03 0.06 0.04 0.04 0.04 0.04 0.06 0.06 −20.46 0.37 −0.02 6.41 0.27 0.350.00 0.23 SEQID-02317 0.02 0.07 0.04 0.05 0.03 0.02 0.08 0.08 −19.610.47 −0.01 6.03 0.22 0.32 0.21 0.22 SEQID-02318 0.04 0.01 0.02 0.04 0.010.00 0.03 0.03 −29.34 0.13 0.03 8.91 0.28 0.30 0.27 0.30 SEQID-023190.02 0.06 0.04 0.03 0.06 0.03 0.05 0.06 −19.82 0.38 −0.01 6.24 0.20 0.320.00 0.22 SEQID-02320 0.05 0.04 0.03 0.03 0.07 0.03 0.03 0.07 −19.930.49 −0.02 5.51 0.20 0.34 0.21 0.21 SEQID-02321 0.01 0.08 0.05 0.09 0.070.01 0.04 0.06 −19.55 0.31 0.00 7.25 0.19 0.34 0.00 0.23 SEQID-023220.02 0.08 0.06 0.08 0.06 0.02 0.02 0.06 −13.94 0.45 0.03 7.94 0.41 0.560.21 0.32 SEQID-02323 0.02 0.08 0.06 0.03 0.04 0.01 0.03 0.04 −21.810.30 −0.03 5.79 0.23 0.33 0.00 0.00 SEQID-02324 0.04 0.06 0.03 0.04 0.060.01 0.03 0.09 −21.10 0.45 0.00 7.46 0.00 0.35 0.21 0.22 SEQID-023250.05 0.07 0.03 0.06 0.05 0.02 0.06 0.06 −19.60 0.34 −0.05 4.53 0.39 0.560.19 0.21 SEQID-02326 0.02 0.05 0.06 0.04 0.05 0.03 0.05 0.05 −22.140.36 −0.02 5.59 0.20 0.33 0.19 0.20 SEQID-02327 0.01 0.07 0.07 0.05 0.090.02 0.05 0.07 −14.97 0.56 0.01 8.44 0.24 0.33 0.00 0.29 SEQID-023280.02 0.04 0.03 0.03 0.08 0.02 0.06 0.05 −21.37 0.41 −0.03 5.10 0.21 0.320.00 0.21 SEQID-02329 0.03 0.06 0.07 0.07 0.08 0.03 0.05 0.06 −16.530.52 −0.01 6.12 0.27 0.35 0.21 0.26 SEQID-02330 0.03 0.06 0.04 0.03 0.050.01 0.08 0.09 −22.17 0.37 −0.02 4.90 0.74 0.83 0.00 0.00 SEQID-023310.01 0.00 0.00 0.07 0.00 0.00 0.00 0.01 −38.09 0.15 0.02 7.57 0.29 0.300.27 0.28 SEQID-02332 0.02 0.05 0.04 0.05 0.09 0.00 0.00 0.07 −13.980.45 −0.03 6.21 0.80 0.83 0.26 0.28 SEQID-02333 0.01 0.09 0.04 0.02 0.060.02 0.07 0.06 −24.33 0.38 −0.07 4.36 0.39 0.46 0.00 0.25 SEQID-023340.02 0.09 0.02 0.07 0.03 0.02 0.07 0.04 −17.50 0.49 0.05 10.21 0.20 0.340.00 0.00 SEQID-02335 0.04 0.05 0.05 0.05 0.04 0.00 0.04 0.07 −19.220.43 0.00 6.65 0.21 0.33 0.20 0.22 SEQID-02336 0.03 0.03 0.02 0.05 0.050.02 0.05 0.06 −24.82 0.37 −0.01 6.33 0.21 0.33 0.20 0.00 SEQID-023370.01 0.07 0.05 0.05 0.07 0.04 0.07 0.07 −19.39 0.29 −0.01 5.93 0.19 0.340.00 0.22 SEQID-02338 0.02 0.07 0.04 0.05 0.04 0.01 0.06 0.08 −19.980.45 −0.01 5.60 0.22 0.35 0.22 0.22 SEQID-02339 0.03 0.06 0.04 0.05 0.040.03 0.05 0.06 −21.72 0.36 −0.03 5.69 0.21 0.33 0.00 0.21 SEQID-023400.02 0.03 0.03 0.05 0.05 0.00 0.06 0.07 −18.32 0.47 0.00 5.95 0.22 0.340.21 0.22 SEQID-02341 0.02 0.11 0.04 0.05 0.05 0.06 0.04 0.07 −14.510.60 −0.01 6.51 0.21 0.33 0.20 0.23 SEQID-02342 0.03 0.09 0.05 0.05 0.040.07 0.06 0.06 −13.27 0.60 0.00 7.04 0.22 0.33 0.00 0.22 SEQID-023430.03 0.14 0.03 0.04 0.06 0.06 0.03 0.06 −12.54 0.77 −0.01 6.51 0.19 0.320.00 0.22 SEQID-02344 0.03 0.09 0.04 0.05 0.05 0.06 0.04 0.05 −12.000.61 0.01 7.52 0.19 0.33 0.00 0.20 SEQID-02345 0.02 0.10 0.04 0.05 0.060.07 0.05 0.05 −11.60 0.64 0.00 7.08 0.19 0.35 0.00 0.21 SEQID-023460.03 0.00 0.00 0.04 0.04 0.00 0.02 0.06 −33.43 0.12 −0.02 5.63 0.41 0.550.23 0.22 SEQID-02347 0.02 0.03 0.01 0.04 0.02 0.01 0.01 0.02 −39.600.07 0.05 10.23 0.25 0.35 0.22 0.00 SEQID-02348 0.04 0.06 0.03 0.05 0.050.03 0.02 0.07 −22.00 0.36 0.03 9.13 0.45 0.64 0.00 0.00 SEQID-023490.04 0.06 0.03 0.05 0.05 0.02 0.04 0.09 −19.04 0.46 0.01 8.10 0.72 0.860.00 0.21 SEQID-02350 0.02 0.06 0.04 0.04 0.05 0.03 0.04 0.04 −23.290.32 0.00 7.11 0.48 0.64 0.00 0.00 SEQID-02351 0.06 0.08 0.02 0.03 0.050.01 0.06 0.04 −18.81 0.53 −0.03 5.29 0.20 0.29 0.21 0.00 SEQID-023520.03 0.02 0.00 0.06 0.02 0.00 0.01 0.03 −30.87 0.09 −0.01 6.28 0.30 0.380.24 0.21 SEQID-02353 0.02 0.03 0.05 0.05 0.07 0.03 0.04 0.11 −20.200.39 0.00 7.27 0.21 0.31 0.22 0.23 SEQID-02354 0.06 0.01 0.03 0.05 0.030.02 0.01 0.04 −28.42 0.26 0.02 9.14 0.29 0.35 0.18 0.26 SEQID-023550.01 0.13 0.00 0.05 0.02 0.02 0.01 0.05 −23.06 0.63 −0.06 4.34 1.00 1.000.27 0.26 SEQID-02356 0.02 0.02 0.06 0.07 0.09 0.04 0.05 0.06 −19.290.23 0.00 6.90 0.24 0.31 0.21 0.24 SEQID-02357 0.03 0.04 0.04 0.05 0.050.02 0.04 0.08 −20.45 0.42 0.03 9.69 0.22 0.33 0.20 0.22 SEQID-023580.04 0.01 0.03 0.06 0.07 0.00 0.04 0.05 −17.94 0.44 −0.01 6.35 0.25 0.340.29 0.23 SEQID-02359 0.02 0.06 0.04 0.09 0.06 0.02 0.05 0.06 −16.620.42 −0.01 6.49 0.48 0.62 0.21 0.21 SEQID-02360 0.03 0.06 0.06 0.07 0.050.04 0.08 0.04 −19.45 0.29 −0.02 5.66 0.24 0.30 0.25 0.24 SEQID-023610.04 0.03 0.03 0.10 0.03 0.00 0.05 0.08 −15.55 0.61 −0.01 5.20 0.24 0.320.24 0.24 SEQID-02362 0.03 0.03 0.03 0.06 0.04 0.01 0.08 0.08 −18.990.37 −0.02 5.25 0.24 0.32 0.24 0.00 SEQID-02363 0.04 0.03 0.02 0.06 0.040.00 0.04 0.09 −16.78 0.53 −0.01 4.90 0.22 0.32 0.26 0.26 SEQID-023640.04 0.05 0.03 0.04 0.06 0.02 0.06 0.06 −18.19 0.40 −0.02 5.63 0.20 0.330.00 0.22 SEQID-02365 0.03 0.03 0.03 0.09 0.08 0.01 0.10 0.03 −14.550.33 −0.01 5.16 0.22 0.30 0.23 0.24 SEQID-02366 0.04 0.09 0.04 0.07 0.040.05 0.05 0.07 −11.27 0.75 −0.02 5.25 0.00 0.31 0.00 0.22 SEQID-023670.03 0.09 0.04 0.06 0.06 0.05 0.04 0.04 −11.91 0.63 0.00 7.04 0.22 0.350.00 0.20 SEQID-02368 0.05 0.09 0.04 0.05 0.05 0.05 0.05 0.05 −10.930.65 0.01 7.57 0.20 0.31 0.00 0.21 SEQID-02369 0.01 0.01 0.05 0.09 0.060.03 0.09 0.05 −19.00 0.25 −0.02 6.21 1.00 1.00 0.23 0.26 SEQID-023700.01 0.12 0.06 0.04 0.08 0.02 0.03 0.03 −13.69 0.41 0.02 7.95 1.00 1.000.21 0.58 SEQID-02371 0.02 0.06 0.03 0.06 0.07 0.04 0.09 0.06 −17.330.41 −0.03 4.66 1.00 1.00 0.22 0.32 SEQID-02372 0.02 0.05 0.03 0.05 0.020.04 0.05 0.13 −15.63 0.68 0.03 9.85 1.00 1.00 0.00 1.00 SEQID-023730.04 0.07 0.01 0.04 0.07 0.02 0.07 0.08 −23.85 0.48 −0.07 4.41 1.00 1.000.25 0.23 SEQID-02374 0.01 0.08 0.03 0.06 0.08 0.04 0.08 0.09 −15.490.50 0.00 7.28 1.00 1.00 0.54 0.20 SEQID-02375 0.03 0.04 0.03 0.07 0.050.03 0.08 0.06 −17.98 0.34 0.01 8.01 0.71 0.80 0.20 0.34 SEQID-023760.01 0.04 0.08 0.07 0.05 0.02 0.06 0.08 −17.15 0.45 0.01 8.40 0.21 0.310.00 0.21 SEQID-02377 0.03 0.05 0.04 0.06 0.04 0.01 0.03 0.05 −19.830.38 0.00 7.06 0.52 0.73 0.20 0.22 SEQID-02378 0.03 0.05 0.04 0.06 0.040.01 0.03 0.04 −19.64 0.38 0.00 7.34 0.52 0.73 0.21 0.22 SEQID-023790.06 0.05 0.07 0.03 0.03 0.00 0.04 0.07 −22.04 0.36 −0.05 4.44 0.26 0.380.00 0.24 SEQID-02380 0.04 0.08 0.04 0.04 0.05 0.01 0.03 0.05 −24.420.37 −0.06 4.36 0.38 0.54 0.22 0.19 SEQID-02381 0.03 0.00 0.00 0.03 0.030.00 0.03 0.03 −36.74 0.12 −0.09 4.39 0.59 0.70 0.25 0.21 SEQID-023820.03 0.05 0.06 0.05 0.06 0.03 0.04 0.08 −18.72 0.43 0.01 7.75 0.00 0.320.00 0.18 SEQID-02383 0.02 0.09 0.02 0.02 0.03 0.02 0.02 0.12 −18.310.58 0.00 7.24 0.28 0.31 0.21 0.25 SEQID-02384 0.03 0.05 0.01 0.05 0.040.01 0.04 0.04 −26.24 0.28 −0.01 6.55 0.19 0.55 0.19 0.17 SEQID-023850.03 0.05 0.02 0.04 0.05 0.01 0.03 0.04 −26.69 0.24 0.01 8.53 0.20 0.550.18 0.17 SEQID-02386 0.04 0.08 0.03 0.04 0.05 0.01 0.06 0.05 −21.500.39 0.01 8.45 0.19 0.34 0.00 0.20 SEQID-02387 0.02 0.01 0.00 0.04 0.030.00 0.01 0.04 −32.95 0.10 −0.04 5.11 0.39 0.55 0.21 0.21 SEQID-023880.03 0.03 0.01 0.04 0.04 0.01 0.03 0.03 −27.94 0.21 −0.02 5.55 0.19 0.530.18 0.18 SEQID-02389 0.05 0.04 0.04 0.05 0.06 0.02 0.06 0.05 −19.680.41 −0.03 5.05 0.19 0.31 0.00 0.20 SEQID-02390 0.03 0.04 0.01 0.04 0.040.01 0.03 0.03 −28.44 0.23 −0.02 5.55 0.19 0.51 0.18 0.19 SEQID-023910.03 0.04 0.01 0.04 0.03 0.01 0.03 0.04 −28.04 0.22 −0.02 5.44 0.18 0.540.18 0.19 SEQID-02392 0.03 0.04 0.01 0.04 0.04 0.01 0.03 0.03 −28.310.24 −0.02 5.66 0.18 0.50 0.17 0.17 SEQID-02393 0.03 0.10 0.02 0.06 0.040.01 0.05 0.05 −19.60 0.46 0.04 9.84 0.21 0.32 0.00 0.20 SEQID-023940.04 0.05 0.03 0.05 0.06 0.02 0.04 0.10 −17.92 0.49 0.02 8.82 0.70 0.860.00 0.20 SEQID-02395 0.02 0.01 0.00 0.05 0.02 0.00 0.01 0.04 −32.330.12 −0.02 5.54 0.38 0.54 0.21 0.19 SEQID-02396 0.05 0.04 0.03 0.04 0.040.01 0.02 0.08 −21.27 0.45 0.01 7.68 0.21 0.33 0.00 0.22 SEQID-023970.04 0.04 0.03 0.04 0.04 0.03 0.04 0.03 −24.38 0.28 −0.03 5.17 0.20 0.360.00 0.19 SEQID-02398 0.01 0.04 0.06 0.04 0.06 0.02 0.04 0.07 −26.130.30 −0.02 5.29 0.00 0.41 0.17 0.18 SEQID-02399 0.03 0.03 0.03 0.06 0.030.03 0.02 0.10 −19.78 0.56 0.02 8.27 0.23 0.32 0.21 0.19 SEQID-024000.02 0.04 0.04 0.06 0.06 0.02 0.05 0.08 −22.74 0.31 −0.01 6.33 0.00 0.340.17 0.19 SEQID-02401 0.05 0.05 0.04 0.05 0.06 0.02 0.06 0.05 −19.470.43 −0.03 5.16 0.21 0.31 0.00 0.22 SEQID-02402 0.01 0.04 0.07 0.06 0.070.02 0.04 0.09 −22.48 0.31 −0.01 5.81 0.00 0.40 0.00 0.18 SEQID-024030.02 0.02 0.03 0.05 0.05 0.02 0.09 0.06 −24.84 0.20 0.03 9.41 0.00 0.340.17 0.18 SEQID-02404 0.01 0.05 0.04 0.06 0.05 0.03 0.06 0.07 −22.260.33 −0.01 6.27 0.18 0.34 0.19 0.19 SEQID-02405 0.08 0.02 0.04 0.06 0.070.03 0.07 0.02 −18.28 0.36 0.01 8.20 0.25 0.28 0.00 0.00 SEQID-024060.04 0.06 0.04 0.04 0.04 0.02 0.01 0.09 −20.16 0.47 0.01 7.53 0.23 0.350.00 0.321 SEQID-02407 0.03 0.01 0.03 0.05 0.03 0.03 0.08 0.04 −24.990.22 0.02 8.88 0.20 0.32 0.00 0.19 SEQID-02408 0.04 0.03 0.04 0.05 0.040.02 0.08 0.04 −24.99 0.20 0.03 9.54 0.19 0.33 0.18 0.18 SEQID-024090.03 0.04 0.03 0.04 0.07 0.02 0.03 0.06 −19.75 0.46 0.02 8.25 0.21 0.320.00 0.21 SEQID-02410 0.02 0.07 0.04 0.04 0.05 0.01 0.05 0.05 −19.790.43 0.02 8.78 0.20 0.36 0.00 0.21 SEQID-02411 0.02 0.00 0.00 0.04 0.030.00 0.03 0.03 −36.78 0.12 −0.09 4.39 0.59 0.70 0.26 0.22 SEQID-024120.04 0.05 0.03 0.06 0.03 0.00 0.05 0.05 −23.93 0.35 −0.01 6.37 0.88 1.000.18 0.21 SEQID-02413 0.02 0.04 0.04 0.05 0.06 0.03 0.04 0.08 −22.250.35 −0.01 6.34 0.18 0.32 0.19 0.20 SEQID-02414 0.03 0.06 0.04 0.04 0.060.04 0.04 0.06 −17.89 0.44 0.01 8.09 0.20 0.32 0.20 0.21 SEQID-024150.03 0.05 0.05 0.03 0.05 0.04 0.02 0.05 −22.74 0.32 0.02 9.12 0.21 0.300.21 0.20 SEQID-02416 0.01 0.02 0.01 0.02 0.02 0.02 0.03 0.02 −37.680.11 0.09 10.58 0.26 0.36 0.24 0.00 SEQID-02417 0.01 0.02 0.01 0.03 0.020.02 0.04 0.02 −37.55 0.11 0.09 10.51 0.26 0.36 0.20 0.00 SEQID-024180.02 0.03 0.07 0.04 0.07 0.03 0.05 0.09 −23.17 0.28 0.00 6.53 0.20 0.340.19 0.23 SEQID-02419 0.01 0.04 0.02 0.05 0.04 0.03 0.03 0.09 −19.870.48 −0.01 6.39 0.70 0.80 0.26 0.22 SEQID-02420 0.03 0.08 0.03 0.02 0.030.02 0.03 0.05 −31.95 0.40 −0.19 3.81 0.21 0.33 0.00 0.23 SEQID-024210.02 0.05 0.03 0.04 0.04 0.01 0.04 0.07 −21.29 0.41 0.00 6.39 0.85 0.960.00 0.22 SEQID-02422 0.04 0.06 0.04 0.04 0.04 0.02 0.06 0.06 −21.280.35 −0.02 5.14 0.19 0.34 0.00 0.20 SEQID-02423 0.04 0.05 0.03 0.06 0.060.02 0.03 0.08 −18.90 0.66 −0.02 5.14 0.19 0.33 0.00 0.20 SEQID-024240.03 0.05 0.05 0.04 0.04 0.03 0.06 0.05 −19.61 0.37 0.00 7.02 0.17 0.340.19 0.00 SEQID-02425 0.02 0.04 0.07 0.06 0.03 0.05 0.04 0.06 −21.890.25 0.02 8.05 0.22 0.31 0.24 0.21 SEQID-02426 0.02 0.04 0.05 0.05 0.060.03 0.05 0.07 −23.80 0.29 −0.02 5.46 0.19 0.32 0.19 0.19 SEQID-024270.02 0.06 0.05 0.05 0.05 0.00 0.03 0.08 −18.62 0.43 0.00 6.55 0.00 0.520.17 0.97 SEQID-02428 0.03 0.07 0.05 0.05 0.04 0.02 0.07 0.05 −21.750.30 0.01 7.98 0.19 0.31 0.00 0.20 SEQID-02429 0.02 0.03 0.04 0.05 0.060.01 0.05 0.07 −18.78 0.43 0.00 6.62 0.19 0.33 0.00 0.23 SEQID-024300.03 0.06 0.06 0.05 0.06 0.00 0.02 0.07 −16.81 0.55 0.02 8.74 0.51 0.690.00 0.00 SEQID-02431 0.02 0.05 0.06 0.07 0.05 0.01 0.04 0.04 −24.730.28 −0.07 4.42 0.20 0.40 0.00 0.22 SEQID-02432 0.04 0.05 0.04 0.05 0.070.03 0.03 0.08 −18.45 0.60 −0.01 5.73 0.19 0.32 0.00 0.20 SEQID-024330.01 0.04 0.05 0.06 0.06 0.02 0.04 0.07 −22.41 0.32 0.01 8.58 0.19 0.350.19 0.20 SEQID-02434 0.03 0.04 0.05 0.05 0.05 0.02 0.04 0.08 −21.070.40 0.03 9.43 0.22 0.34 0.00 0.22 SEQID-02435 0.03 0.05 0.03 0.05 0.030.01 0.04 0.07 −21.68 0.43 −0.05 4.55 0.82 0.96 0.21 0.22 SEQID-024360.04 0.05 0.04 0.04 0.03 0.02 0.05 0.07 −22.82 0.38 0.00 6.73 0.21 0.320.00 0.21 SEQID-02437 0.02 0.07 0.04 0.03 0.06 0.00 0.04 0.08 −17.520.62 0.03 8.71 0.23 0.31 0.00 0.22 SEQID-02438 0.04 0.02 0.02 0.04 0.020.01 0.02 0.03 −32.14 0.15 0.06 10.17 0.26 0.31 0.26 0.00 SEQID-024390.01 0.07 0.04 0.05 0.04 0.03 0.07 0.05 −21.60 0.24 0.06 8.37 0.21 0.320.23 0.23 SEQID-02440 0.03 0.05 0.03 0.04 0.07 0.01 0.04 0.06 −23.370.33 −0.01 5.71 0.72 0.89 0.19 0.21 SEQID-02441 0.03 0.04 0.05 0.10 0.070.01 0.04 0.06 −23.33 0.22 0.01 8.53 0.19 0.40 0.19 0.19 SEQID-024420.00 0.07 0.02 0.08 0.09 0.02 0.06 0.05 −17.94 0.30 0.01 8.88 0.20 0.320.00 0.00 SEQID-02443 0.04 0.05 0.089 0.07 0.05 0.01 0.06 0.03 −20.790.18 0.04 9.80 0.18 0.34 0.00 0.23 SEQID-02444 0.04 0.05 0.04 0.06 0.040.03 0.05 0.05 −19.86 0.39 0.03 9.43 0.22 0.31 0.00 0.21 SEQID-024450.01 0.03 0.10 0.05 0.07 0.02 0.03 0.06 −21.39 0.27 0.00 6.99 0.20 0.430.20 0.22 SEQID-02446 0.02 0.05 0.03 0.05 0.07 0.01 0.03 0.06 −22.590.34 −0.02 5.16 0.74 0.93 0.21 0.22 SEQID-02447 0.04 0.07 0.03 0.03 0.060.00 0.03 0.07 −17.51 0.50 0.01 7.98 0.23 0.31 0.00 0.00 SEQID-024480.05 0.06 0.07 0.02 0.04 0.00 0.02 0.05 −23.59 0.32 −0.04 4.68 0.31 0.480.00 0.22 SEQID-02449 0.02 0.05 0.03 0.05 0.06 0.00 0.06 0.06 −18.880.43 0.02 9.26 0.19 0.31 0.00 0.22 SEQID-02450 0.02 0.04 0.04 0.04 0.050.02 0.04 0.05 −22.04 0.28 0.01 8.21 0.37 0.54 0.00 0.20 SEQID-024510.03 0.04 0.05 0.03 0.06 0.00 0.04 0.08 −19.05 0.48 −0.04 4.75 0.22 0.330.20 0.20 SEQID-02452 0.02 0.02 0.07 0.06 0.09 0.01 0.03 0.10 −21.920.31 0.01 9.07 0.19 0.34 0.19 0.19 SEQID-02453 0.02 0.06 0.03 0.05 0.030.05 0.02 0.08 −16.92 0.54 0.04 9.64 0.23 0.33 0.20 0.21 SEQID-024540.03 0.08 0.02 0.04 0.03 0.03 0.07 0.07 −17.65 0.55 0.07 10.22 0.23 0.310.00 0.00 SEQID-02455 0.05 0.07 0.05 0.05 0.07 0.01 0.05 0.06 −18.760.33 −0.04 4.68 0.39 0.53 0.00 0.21 SEQID-02456 0.03 0.04 0.02 0.05 0.060.02 0.04 0.07 −18.79 0.48 0.01 7.64 0.19 0.33 0.00 0.22 SEQID-024570.04 0.05 0.05 0.04 0.05 0.01 0.04 0.07 −21.29 0.44 0.00 6.93 0.20 0.330.19 0.20 SEQID-02458 0.02 0.06 0.04 0.05 0.03 0.02 0.05 0.06 −20.310.48 0.00 7.09 0.18 0.32 0.20 0.19 SEQID-02459 0.03 0.06 0.03 0.06 0.040.02 0.05 0.05 −21.32 0.46 −0.02 5.69 0.00 0.33 0.00 0.19 SEQID-024600.01 0.04 0.03 0.06 0.07 0.02 0.04 0.07 −23.81 0.32 −0.01 6.06 0.00 0.360.00 0.00 SEQID-02461 0.03 0.03 0.04 0.06 0.05 0.00 0.05 0.08 −19.820.44 0.00 7.49 0.21 0.33 0.00 0.23 SEQID-02462 0.04 0.06 0.04 0.04 0.040.02 0.03 0.06 −22.56 0.35 −0.01 6.40 0.42 0.65 0.00 0.19 SEQID-024630.02 0.06 0.04 0.04 0.06 0.01 0.06 0.07 −19.71 0.37 −0.05 4.70 0.93 1.000.19 0.32 SEQID-02464 0.03 0.04 0.01 0.05 0.04 0.00 0.05 0.05 −24.760.39 −0.01 5.89 0.22 0.33 0.00 0.20 SEQID-02465 0.03 0.06 0.05 0.04 0.040.01 0.03 0.05 −21.99 0.39 −0.03 4.94 0.20 0.33 0.00 0.22 SEQID-024660.02 0.06 0.04 0.06 0.06 0.02 0.04 0.07 −20.05 0.45 0.00 7.09 0.18 0.990.18 0.20 SEQID-02467 0.03 0.04 0.04 0.05 0.05 0.02 0.05 0.06 −19.090.42 −0.01 6.58 0.19 0.33 0.19 0.20 SEQID-02468 0.03 0.06 0.05 0.03 0.040.00 0.10 0.05 −24.58 0.42 −0.01 5.16 0.26 0.29 0.00 0.00 SEQID-024690.02 0.06 0.09 0.09 0.05 0.05 0.04 0.05 −20.66 0.25 0.00 6.69 0.22 0.310.00 0.22 SEQID-02470 0.02 0.03 0.04 0.05 0.03 0.04 0.04 0.05 −22.960.32 −0.01 6.64 0.21 0.31 0.00 0.20 SEQID-02471 0.03 0.02 0.03 0.07 0.040.02 0.05 0.06 −23.84 0.29 −0.01 5.78 0.19 0.33 0.00 0.00 SEQID-024720.03 0.04 0.04 0.05 0.04 0.02 0.03 0.09 −20.58 0.56 0.00 7.45 0.25 0.330.00 0.00 SEQID-02473 0.04 0.07 0.03 0.05 0.06 0.05 0.04 0.05 −18.230.38 0.02 8.89 0.19 0.32 0.00 0.00 SEQID-02474 0.03 0.03 0.02 0.05 0.040.00 0.07 0.04 −25.38 0.35 0.00 7.40 0.21 0.33 0.00 0.00 SEQID-024750.02 0.06 0.04 0.03 0.05 0.03 0.05 0.07 −20.38 0.41 0.01 8.20 0.21 0.320.00 0.22 SEQID-02476 0.04 0.05 0.02 0.03 0.06 0.02 0.03 0.07 −21.760.49 −0.01 5.82 0.21 0.33 0.21 0.20 SEQID-02477 0.02 0.04 0.08 0.05 0.050.02 0.04 0.04 −20.44 0.24 0.01 8.55 0.20 0.36 0.20 0.21 SEQID-024780.02 0.09 0.04 0.05 0.06 0.01 0.05 0.06 −17.07 0.48 0.01 8.48 0.20 0.360.00 0.21 SEQID-02479 0.02 0.05 0.07 0.07 0.05 0.02 0.02 0.05 −21.000.33 −0.02 5.10 0.18 0.33 0.20 0.21 SEQID-02480 0.03 0.04 0.02 0.04 0.050.01 0.05 0.05 −28.79 0.90 −0.05 4.73 0.65 0.86 0.00 0.21 SEQID-024810.03 0.02 0.03 0.09 0.07 0.00 0.06 0.06 −23.72 0.21 0.14 10.93 0.26 0.300.00 0.21 SEQID-02482 0.05 0.07 0.03 0.02 0.05 0.00 0.05 0.06 −24.450.38 −0.05 4.74 0.42 0.52 0.00 0.22 SEQID-02483 0.02 0.02 0.02 0.06 0.040.01 0.08 0.05 −24.51 0.30 −0.06 4.50 0.25 0.32 0.22 0.00 SEQID-024840.03 0.07 0.04 0.04 0.04 0.03 0.05 0.04 −25.47 0.32 −0.03 4.91 0.22 0.320.00 0.23 SEQID-02485 0.02 0.05 0.04 0.05 0.07 0.00 0.05 0.04 −19.780.44 0.00 6.90 0.20 0.30 0.00 0.00 SEQID-02486 0.04 0.08 0.05 0.05 0.040.03 0.08 0.07 −15.73 0.57 0.04 9.53 0.21 0.30 0.00 0.00 SEQID-024870.03 0.05 0.05 0.04 0.04 0.03 0.05 0.06 −19.73 0.41 0.00 7.19 0.21 0.330.00 0.00 SEQID-02488 0.02 0.05 0.05 0.04 0.04 0.03 0.05 0.06 −20.630.35 −0.01 6.50 0.21 0.33 0.00 0.19 SEQID-02489 0.03 0.07 0.02 0.03 0.040.02 0.04 0.05 −24.46 0.45 0.00 6.80 0.21 0.32 0.00 0.20 SEQID-024900.03 0.07 0.03 0.08 0.04 0.02 0.05 0.04 −21.89 0.31 0.00 7.33 0.22 0.360.20 0.21 SEQID-02491 0.03 0.05 0.04 0.04 0.05 0.00 0.04 0.08 −18.410.48 0.03 9.56 0.19 0.35 0.00 0.21 SEQID-02492 0.02 0.04 0.07 0.05 0.040.01 0.04 0.05 −20.66 0.34 −0.01 5.44 0.26 0.55 0.21 0.30 SEQID-024930.03 0.05 0.03 0.06 0.04 0.02 0.05 0.05 −21.97 0.38 −0.02 5.70 0.19 0.340.00 0.20 SEQID-02494 0.01 0.06 0.04 0.06 0.04 0.01 0.06 0.07 −17.070.38 0.02 9.01 0.47 0.64 0.21 0.21 SEQID-02495 0.01 0.06 0.04 0.06 0.040.01 0.06 0.07 −16.80 0.38 0.02 8.77 0.46 0.63 0.20 0.21 SEQID-024960.01 0.07 0.04 0.05 0.03 0.01 0.05 0.06 −16.41 0.40 0.03 9.41 0.45 0.610.21 0.21 SEQID-02497 0.01 0.08 0.04 0.07 0.04 0.01 0.06 0.06 −16.250.37 0.02 9.18 0.45 0.62 0.00 0.21 SEQID-02498 0.02 0.07 0.04 0.04 0.030.01 0.05 0.06 −16.80 0.40 0.02 8.96 0.45 0.61 0.00 0.21 SEQID-024990.01 0.06 0.03 0.06 0.04 0.01 0.06 0.07 −17.37 0.42 0.02 8.64 0.45 0.600.00 0.22 SEQID-02500 0.04 0.07 0.04 0.05 0.04 0.03 0.07 0.06 −21.430.31 0.00 6.82 0.19 0.33 0.00 0.20 SEQID-02501 0.01 0.07 0.04 0.04 0.030.01 0.05 0.06 −17.67 0.44 0.03 9.55 0.42 0.56 0.00 0.22 SEQID-025020.02 0.07 0.04 0.06 0.04 0.02 0.03 0.07 −16.73 0.44 0.02 8.95 0.41 0.600.21 0.22 SEQID-02503 0.01 0.07 0.04 0.04 0.04 0.01 0.04 0.05 −17.570.40 0.04 9.98 0.41 0.59 0.00 0.21 SEQID-02504 0.04 0.07 0.05 0.06 0.030.03 0.07 0.06 −20.04 0.31 −0.02 5.99 0.19 0.36 0.00 0.21 SEQID-025050.02 0.06 0.04 0.07 0.04 0.03 0.06 0.07 −18.61 0.37 −0.01 6.20 0.19 0.340.00 0.20 SEQID-02506 0.03 0.05 0.05 0.04 0.04 0.02 0.05 0.07 −19.040.45 0.01 8.22 0.21 0.33 0.20 0.21 SEQID-02507 0.04 0.05 0.04 0.04 0.050.01 0.03 0.08 −19.62 0.43 −0.01 6.31 0.20 0.35 0.00 0.21 SEQID-025080.03 0.06 0.04 0.04 0.05 0.02 0.06 0.05 −20.08 0.42 −0.01 6.59 0.19 0.310.00 0.21 SEQID-02509 0.04 0.06 0.04 0.05 0.06 0.01 0.05 0.05 −19.780.42 −0.02 5.49 0.20 0.30 0.00 0.21 SEQID-02510 0.03 0.04 0.04 0.06 0.040.01 0.06 0.06 −19.00 0.46 0.00 7.04 0.21 0.32 0.00 0.21 SEQID-025110.03 0.06 0.04 0.04 0.04 0.02 0.06 0.05 −20.23 0.42 −0.01 6.35 0.20 0.310.00 0.20 SEQID-02512 0.02 0.06 0.04 0.04 0.04 0.02 0.07 0.06 −20.160.41 −0.01 6.52 0.20 0.34 0.00 0.22 SEQID-02513 0.01 0.08 0.03 0.05 0.020.01 0.10 0.06 −9.08 0.66 0.01 8.91 0.31 0.41 0.21 0.20 SEQID-02514 0.020.05 0.04 0.05 0.04 0.03 0.05 0.07 −21.93 0.35 −0.02 5.75 0.19 0.36 0.000.20 SEQID-02515 0.02 0.05 0.03 0.03 0.05 0.01 0.04 0.07 −25.25 0.39−0.03 4.82 0.89 0.99 0.00 0.21 SEQID-02516 0.04 0.05 0.05 0.06 0.05 0.020.05 0.06 −16.46 0.49 0.01 8.09 0.23 0.33 0.00 0.20 SEQID-02517 0.030.05 0.03 0.05 0.06 0.03 0.04 0.10 −19.93 0.49 0.01 8.07 0.88 0.95 0.000.21 SEQID-02518 0.04 0.04 0.05 0.04 0.05 0.02 0.05 0.09 −17.47 0.550.04 9.88 0.22 0.34 0.22 0.22 SEQID-02519 0.01 0.05 0.04 0.05 0.03 0.010.03 0.06 −25.87 0.41 0.01 8.23 0.37 0.51 0.18 0.21 SEQID-02520 0.020.04 0.04 0.05 0.07 0.00 0.01 0.09 −21.36 0.39 −0.02 4.86 0.46 0.77 0.000.22 SEQID-02521 0.02 0.07 0.04 0.07 0.05 0.01 0.03 0.07 −17.87 0.360.01 8.44 0.22 0.44 0.20 0.22 SEQID-02522 0.03 0.04 0.05 0.04 0.06 0.010.04 0.08 −22.21 0.39 0.03 9.56 0.22 0.35 0.21 0.22 SEQID-02523 0.010.07 0.04 0.05 0.05 0.01 0.05 0.06 −17.00 0.39 0.01 8.01 0.43 0.60 0.200.21 SEQID-02524 0.07 0.04 0.04 0.08 0.01 0.01 0.07 0.04 −19.56 0.330.00 7.60 0.36 0.49 0.25 0.24 SEQID-02525 0.01 0.03 0.04 0.05 0.06 0.010.05 0.07 −19.79 0.39 0.01 8.33 0.21 0.33 0.00 0.00 SEQID-02526 0.040.05 0.04 0.03 0.03 0.01 0.02 0.11 −19.49 0.55 −0.01 6.43 0.26 0.35 0.200.20 SEQID-02527 0.02 0.05 0.05 0.05 0.03 0.01 0.06 0.05 −17.50 0.460.00 6.62 0.21 0.32 0.00 0.22 SEQID-02528 0.01 0.08 0.05 0.04 0.03 0.010.05 0.07 −23.43 0.40 −0.04 4.76 0.24 0.63 0.19 0.21 SEQID-02529 0.040.02 0.05 0.04 0.03 0.02 0.05 0.09 −15.87 0.52 0.02 7.90 1.00 1.00 0.270.32 SEQID-02530 0.02 0.06 0.03 0.05 0.06 0.03 0.04 0.10 −20.63 0.470.00 6.80 0.89 0.96 0.23 0.00 SEQID-02531 0.02 0.06 0.04 0.07 0.03 0.010.03 0.07 −23.43 0.45 0.00 7.26 0.39 0.54 0.22 0.23 SEQID-02532 0.050.05 0.04 0.04 0.05 0.02 0.04 0.08 −21.12 0.40 −0.01 6.03 0.20 0.33 0.000.21 SEQID-02533 0.04 0.06 0.03 0.04 0.05 0.01 0.05 0.08 −21.73 0.43−0.02 5.23 0.22 0.33 0.00 0.21 SEQID-02534 0.04 0.07 0.03 0.04 0.05 0.010.04 0.07 −21.79 0.40 −0.02 5.35 0.22 0.33 0.00 0.20 SEQID-02535 0.020.05 0.04 0.04 0.06 0.01 0.02 0.09 −20.07 0.56 −0.01 5.57 0.24 0.36 0.000.22 SEQID-02536 0.05 0.05 0.04 0.05 0.04 0.02 0.04 0.08 −21.12 0.40−0.01 6.03 0.19 0.33 0.00 0.21 SEQID-02537 0.05 0.08 0.04 0.06 0.03 0.010.06 0.06 −7.72 0.63 0.02 8.14 0.33 0.48 0.27 0.26 SEQID-02538 0.02 0.040.04 0.07 0.06 0.01 0.04 0.07 −19.34 0.40 0.00 6.93 0.20 0.33 0.00 0.20SEQID-02539 0.01 0.05 0.05 0.05 0.05 0.01 0.03 0.08 −20.15 0.43 −0.025.26 0.24 0.32 0.00 0.22 SEQID-02540 0.03 0.03 0.06 0.04 0.04 0.02 0.060.10 −15.06 0.53 0.02 8.09 1.00 1.00 0.28 0.33 SEQID-02541 0.02 0.050.04 0.05 0.06 0.01 0.03 0.08 −19.70 0.53 0.00 6.55 0.23 0.33 0.22 0.21SEQID-02542 0.03 0.05 0.03 0.06 0.06 0.03 0.04 0.09 −19.94 0.46 0.007.13 0.93 0.99 0.00 0.21 SEQID-02543 0.03 0.05 0.04 0.05 0.05 0.01 0.060.05 −18.88 0.46 0.00 6.64 0.21 0.31 0.00 0.21 SEQID-02544 0.02 0.070.06 0.05 0.06 0.03 0.06 0.08 −15.70 0.45 0.01 8.78 0.21 0.33 0.00 0.21SEQID-02545 0.05 0.03 0.06 0.04 0.02 0.02 0.07 0.09 −15.58 0.53 0.028.09 1.00 1.00 0.29 0.33 SEQID-02546 0.07 0.04 0.07 0.03 0.03 0.01 0.060.09 −14.38 0.66 0.03 8.41 1.00 1.00 0.27 0.30 SEQID-02547 0.01 0.060.04 0.06 0.02 0.02 0.07 0.08 −7.89 0.67 0.02 8.47 0.32 0.46 0.25 0.23SEQID-02548 0.03 0.04 0.04 0.05 0.05 0.03 0.03 0.07 −20.17 0.43 0.029.64 0.00 0.30 0.00 0.00 SEQID-02549 0.05 0.04 0.05 0.05 0.06 0.02 0.060.06 −19.73 0.44 −0.03 5.16 0.20 0.34 0.00 0.21 SEQID-02550 0.05 0.040.05 0.04 0.03 0.01 0.05 0.09 −14.39 0.68 0.01 7.57 0.34 0.40 0.27 0.37SEQID-02551 0.04 0.08 0.05 0.05 0.04 0.04 0.07 0.06 −18.24 0.37 −0.035.44 0.20 0.34 0.00 0.22 SEQID-02552 0.01 0.06 0.03 0.06 0.01 0.01 0.100.05 −9.62 0.60 0.02 9.47 0.29 0.40 0.26 0.23 SEQID-02553 0.08 0.05 0.050.07 0.02 0.02 0.04 0.05 −9.85 0.49 0.02 7.95 0.35 0.49 0.30 0.29SEQID-02554 0.01 0.07 0.04 0.06 0.03 0.02 0.098 0.07 −7.89 0.65 0.028.46 0.31 0.48 0.26 0.24 SEQID-02555 0.04 0.07 0.06 0.04 0.04 0.03 0.060.06 −21.89 0.35 0.00 6.39 0.21 0.35 0.00 0.20 SEQID-02556 0.05 0.050.02 0.04 0.04 0.02 0.04 0.07 −18.88 0.52 0.03 8.84 0.24 0.31 0.00 0.23SEQID-02557 0.06 0.03 0.04 0.06 0.02 0.01 0.04 0.09 −15.43 0.71 0.017.57 0.33 0.39 0.26 0.38 SEQID-02558 0.01 0.07 0.03 0.05 0.02 0.00 0.100.06 −9.17 0.67 0.02 8.91 0.31 0.41 0.26 0.23 SEQID-02559 0.01 0.07 0.040.06 0.02 0.02 0.10 0.04 −10.06 0.62 0.00 7.33 0.28 0.36 0.22 0.23SEQID-02560 0.05 0.04 0.05 0.06 0.05 0.02 0.06 0.07 −19.68 0.43 −0.035.15 0.21 0.32 0.00 0.19 SEQID-02561 0.03 0.06 0.04 0.06 0.05 0.02 0.050.08 −15.24 0.55 0.00 7.05 0.24 0.55 0.19 0.22 SEQID-02562 0.04 0.030.05 0.06 0.06 0.02 0.03 0.09 −16.87 0.54 −0.01 5.97 0.25 0.35 0.21 0.21SEQID-02563 0.02 0.04 0.08 0.06 0.05 0.05 0.10 0.06 −16.23 0.41 0.007.12 0.70 0.91 0.00 0.21 SEQID-02564 0.02 0.06 0.05 0.03 0.03 0.06 0.040.06 −20.60 0.31 −0.01 6.79 0.22 0.32 0.22 0.23 SEQID-02565 0.04 0.070.07 0.04 0.03 0.03 0.06 0.06 −21.89 0.34 0.00 6.69 0.21 0.38 0.21 0.21SEQID-02566 0.03 0.07 0.04 0.07 0.06 0.01 0.05 0.08 −18.93 0.44 −0.025.28 0.21 0.33 0.00 0.21 SEQID-02567 0.04 0.03 0.06 0.04 0.03 0.03 0.080.08 −15.22 0.52 0.01 7.31 1.00 1.00 0.26 0.32 SEQID-02568 0.01 0.070.06 0.03 0.04 0.01 0.06 0.07 −15.31 0.51 −0.03 4.64 0.26 0.35 0.00 0.24SEQID-02569 0.01 0.04 0.03 0.09 0.06 0.06 0.05 0.08 −16.43 0.41 −0.016.41 0.21 0.32 0.00 0.22 SEQID-02570 0.03 0.04 0.05 0.05 0.06 0.03 0.040.07 −19.99 0.46 0.00 7.01 0.21 0.34 0.22 0.21 SEQID-02571 0.02 0.040.03 0.05 0.04 0.02 0.02 0.06 −28.49 0.36 −0.03 5.45 0.22 0.43 0.00 0.20SEQID-02572 0.03 0.04 0.03 0.04 0.06 0.01 0.09 0.06 −22.92 0.37 −0.034.84 0.71 0.91 0.00 0.21 SEQID-02573 0.03 0.05 0.02 0.05 0.04 0.02 0.040.05 −28.14 0.31 −0.05 4.69 0.66 0.83 0.00 0.20 SEQID-02574 0.01 0.070.03 0.06 0.03 0.01 0.09 0.06 −8.93 0.63 0.01 8.42 0.31 0.42 0.23 0.25SEQID-02575 0.01 0.04 0.03 0.06 0.05 0.04 0.02 0.12 −17.90 0.51 −0.015.15 0.87 0.93 0.00 0.00 SEQID-02576 0.02 0.04 0.05 0.04 0.04 0.01 0.040.09 −19.24 0.34 0.13 11.57 0.00 0.35 0.00 0.24 SEQID-02577 0.02 0.050.04 0.02 0.06 0.01 0.09 0.06 −23.20 0.38 −0.01 5.31 1.00 1.00 0.20 0.22SEQID-02578 0.04 0.07 0.06 0.04 0.04 0.03 0.06 0.06 −22.11 0.34 0.006.40 0.21 0.33 0.00 0.21 SEQID-02579 0.03 0.04 0.03 0.05 0.04 0.02 0.050.08 −19.55 0.44 −0.02 5.23 0.88 0.98 0.20 0.21 SEQID-02580 0.03 0.060.06 0.05 0.04 0.04 0.06 0.07 −17.64 0.45 −0.01 6.24 0.20 0.34 0.00 0.22SEQID-02581 0.03 0.04 0.07 0.04 0.03 0.03 0.05 0.08 −21.18 0.39 −0.025.14 0.20 0.34 0.00 0.22 SEQID-02582 0.04 0.07 0.05 0.05 0.02 0.06 0.050.07 −20.45 0.39 0.00 6.81 0.23 0.33 0.19 0.23 SEQID-02583 0.02 0.040.05 0.05 0.04 0.02 0.03 0.07 −21.54 0.36 0.11 11.32 0.21 0.39 0.00 0.19SEQID-02584 0.03 0.07 0.04 0.04 0.02 0.04 0.04 0.09 −19.60 0.45 0.007.77 0.00 0.32 0.26 0.22 SEQID-02585 0.03 0.03 0.01 0.05 0.04 0.01 0.070.05 −25.84 0.30 −0.06 4.49 0.22 0.32 0.00 0.00 SEQID-02586 0.03 0.030.02 0.06 0.05 0.01 0.07 0.04 −26.08 0.30 −0.06 4.46 0.24 0.32 0.00 0.00SEQID-02587 0.02 0.07 0.05 0.07 0.05 0.03 0.03 0.08 −16.51 0.51 −0.016.05 0.26 0.48 0.00 0.23 SEQID-02588 0.02 0.04 0.04 0.05 0.07 0.00 0.010.08 −22.86 0.38 −0.06 4.32 0.47 0.66 0.22 0.23 SEQID-02589 0.05 0.050.05 0.05 0.04 0.02 0.04 0.04 −18.82 0.37 0.02 8.39 0.22 0.35 0.20 0.23SEQID-02590 0.04 0.03 0.04 0.06 0.04 0.02 0.06 0.07 −20.00 0.41 0.007.05 0.22 0.34 0.20 0.22 SEQID-02591 0.03 0.04 0.04 0.05 0.05 0.00 0.050.07 −18.93 0.47 −0.01 5.90 0.21 0.33 0.00 0.22 SEQID-02592 0.02 0.040.05 0.04 0.06 0.00 0.04 0.08 −18.09 0.47 −0.01 6.31 0.21 0.35 0.21 0.22SEQID-02593 0.04 0.04 0.06 0.05 0.05 0.00 0.04 0.08 −17.29 0.50 0.018.18 0.20 0.33 0.19 0.21 SEQID-02594 0.03 0.05 0.04 0.06 0.06 0.03 0.050.07 −19.28 0.43 −0.01 6.23 0.87 0.96 0.00 0.20 SEQID-02595 0.03 0.060.05 0.05 0.05 0.02 0.05 0.08 −18.26 0.43 −0.02 5.89 0.20 0.34 0.00 0.21SEQID-02596 0.02 0.03 0.05 0.07 0.04 0.01 0.03 0.07 −24.35 0.36 −0.104.09 0.19 0.40 0.20 0.19 SEQID-02597 0.02 0.02 0.03 0.02 0.08 0.00 0.040.05 −25.27 0.34 −0.01 5.85 0.00 0.33 0.00 0.00 SEQID-02598 0.02 0.090.03 0.03 0.03 0.02 0.06 0.07 −24.82 0.35 −0.07 4.28 0.38 0.44 0.24 0.24SEQID-02599 0.02 0.05 0.02 0.05 0.03 0.07 0.04 0.05 −10.38 0.87 0.039.59 0.24 0.35 0.28 0.24 SEQID-02600 0.01 0.04 0.10 0.07 0.05 0.03 0.040.08 −17.05 0.50 0.02 8.49 0.30 0.39 0.00 1.00 SEQID-02601 0.04 0.050.04 0.04 0.04 0.01 0.04 0.08 −21.61 0.44 0.05 10.15 0.21 0.31 0.00 0.21SEQID-02602 0.03 0.04 0.07 0.03 0.05 0.05 0.04 0.06 −17.05 0.50 −0.044.61 0.20 0.35 0.20 0.00 SEQID-02603 0.02 0.06 0.05 0.05 0.03 0.04 0.040.08 −20.46 0.47 0.01 8.42 0.42 0.69 0.22 0.20 SEQID-02604 0.03 0.030.04 0.03 0.04 0.02 0.06 0.06 −19.79 0.39 0.00 7.19 0.21 0.31 0.00 0.19SEQID-02605 0.02 0.03 0.03 0.05 0.05 0.00 0.03 0.09 −24.17 0.42 0.007.09 0.21 0.33 0.00 0.21 SEQID-02606 0.03 0.05 0.03 0.04 0.05 0.02 0.050.07 −24.29 0.30 0.13 10.75 0.67 0.75 0.00 0.20 SEQID-02607 0.03 0.030.04 0.07 0.03 0.01 0.02 0.07 −22.97 0.41 0.01 8.58 0.41 0.60 0.21 0.23SEQID-02608 0.02 0.06 0.05 0.05 0.04 0.00 0.05 0.06 −20.67 0.39 −0.016.22 0.20 0.34 0.00 0.21 SEQID-02609 0.03 0.06 0.05 0.07 0.04 0.01 0.040.07 −17.99 0.49 −0.01 6.39 0.21 0.38 0.00 0.21 SEQID-02610 0.01 0.080.05 0.05 0.05 0.01 0.04 0.05 −22.39 0.44 −0.06 4.53 0.21 0.51 0.00 0.21SEQID-02611 0.02 0.05 0.04 0.07 0.05 0.02 0.04 0.07 −21.82 0.36 0.006.87 0.19 0.32 0.00 0.21 SEQID-02612 0.03 0.05 0.07 0.04 0.05 0.02 0.040.08 −21.82 0.35 −0.01 6.40 0.86 0.93 0.00 0.00 SEQID-02613 0.03 0.050.04 0.05 0.02 0.02 0.04 0.06 −22.91 0.24 0.14 11.03 0.22 0.31 0.24 0.26SEQID-02614 0.02 0.04 0.05 0.02 0.04 0.02 0.02 0.07 −25.19 0.35 0.1411.09 0.22 0.31 0.20 0.22 SEQID-02615 0.02 0.05 0.02 0.03 0.06 0.00 0.090.04 −26.16 0.26 0.03 9.40 0.22 0.31 0.00 0.00 SEQID-02616 0.02 0.060.05 0.04 0.04 0.06 0.03 0.07 −20.47 0.36 0.01 7.28 0.19 0.33 0.22 0.21SEQID-02617 0.02 0.09 0.05 0.06 0.05 0.02 0.07 0.08 −14.92 0.47 0.007.33 0.52 0.70 0.00 0.21 SEQID-02618 0.02 0.03 0.03 0.03 0.03 0.00 0.020.08 −24.23 0.41 −0.01 6.17 0.22 0.38 0.39 0.21 SEQID-02619 0.04 0.010.06 0.04 0.05 0.01 0.06 0.03 −16.32 0.61 0.01 7.57 0.51 0.55 0.26 0.56SEQID-02620 0.02 0.07 0.05 0.06 0.03 0.03 0.00 0.12 −27.11 0.32 0.006.56 0.75 0.85 0.19 0.24 SEQID-02621 0.02 0.06 0.04 0.04 0.04 0.03 0.100.05 −17.30 0.52 −0.01 6.60 0.36 0.50 0.00 0.20 SEQID-02622 0.03 0.040.05 0.06 0.04 0.00 0.05 0.10 −20.38 0.59 −0.02 5.14 0.20 0.53 0.21 0.23SEQID-02623 0.01 0.09 0.05 0.07 0.06 0.02 0.06 0.04 −20.14 0.28 −0.025.66 0.23 0.31 0.00 0.00 SEQID-02624 0.03 0.03 0.05 0.05 0.04 0.05 0.060.06 −19.35 0.33 −0.01 6.65 0.21 0.32 0.00 0.23 SEQID-02625 0.04 0.050.06 0.05 0.05 0.01 0.04 0.07 −16.45 0.59 0.04 10.08 0.21 0.34 0.00 0.22SEQID-02626 0.05 0.07 0.03 0.05 0.05 0.02 0.05 0.06 −19.72 0.35 −0.064.46 0.40 0.54 0.00 0.21 SEQID-02627 0.03 0.06 0.04 0.06 0.04 0.01 0.060.08 −19.97 0.39 −0.05 4.57 0.81 0.90 0.23 0.22 SEQID-02628 0.03 0.040.05 0.04 0.05 0.01 0.06 0.08 −17.24 0.44 0.01 8.43 0.22 0.34 0.21 0.22SEQID-02629 0.03 0.05 0.05 0.05 0.05 0.02 0.09 0.07 −15.14 0.55 0.007.08 0.28 0.38 0.21 0.22 SEQID-02630 0.02 0.03 0.05 0.06 0.04 0.02 0.040.06 −18.89 0.43 0.00 6.66 0.21 0.32 0.00 0.21 SEQID-02631 0.03 0.070.03 0.06 0.05 0.02 0.05 0.06 −24.34 0.34 0.02 9.28 0.38 0.61 0.00 0.21SEQID-02632 0.02 0.04 0.04 0.05 0.04 0.01 0.04 0.06 −21.94 0.46 −0.025.13 0.20 0.35 0.18 0.20 SEQID-02633 0.05 0.05 0.06 0.03 0.03 0.00 0.050.06 −23.57 0.36 0.10 10.85 0.23 0.29 0.20 0.25 SEQID-02634 0.01 0.090.06 0.08 0.03 0.03 0.00 0.06 −25.01 0.26 −0.01 5.86 0.72 0.85 0.18 0.22SEQID-02635 0.01 0.07 0.05 0.03 0.06 0.01 0.04 0.06 −21.44 0.34 0.1811.28 0.21 0.31 0.26 0.22 SEQID-02636 0.04 0.05 0.02 0.03 0.05 0.02 0.020.06 −26.57 0.30 0.13 11.42 0.24 0.32 0.20 0.23 SEQID-02637 0.02 0.030.04 0.05 0.03 0.01 0.05 0.05 −24.26 0.31 0.12 10.98 0.31 0.30 0.20 0.23SEQID-02638 0.02 0.02 0.02 0.05 0.05 0.03 0.05 0.06 −25.95 0.18 0.1311.09 0.23 0.34 0.00 0.19 SEQID-02639 0.03 0.04 0.03 0.08 0.05 0.02 0.060.08 −23.36 0.38 −0.08 4.12 0.39 0.54 0.00 0.00 SEQID-02640 0.02 0.060.05 0.01 0.05 0.01 0.07 0.07 −21.08 0.37 0.00 7.15 0.20 0.30 0.00 0.20SEQID-02641 0.02 0.02 0.02 0.05 0.05 0.03 0.05 0.05 −25.83 0.18 0.1311.09 0.23 0.33 0.00 0.20 SEQID-02642 0.02 0.05 0.03 0.04 0.05 0.00 0.030.05 −27.95 0.23 0.16 11.35 0.20 0.33 0.17 0.18 SEQID-02643 0.03 0.050.02 0.04 0.05 0.02 0.03 0.08 −25.27 0.31 0.08 10.53 0.20 0.30 0.00 0.00SEQID-02644 0.02 0.06 0.05 0.03 0.06 0.02 0.02 0.10 −21.54 0.40 0.0910.94 0.22 0.33 0.20 0.25 SEQID-02645 0.03 0.05 0.05 0.04 0.05 0.01 0.050.06 −19.10 0.45 −0.01 5.83 0.26 0.36 0.00 0.00 SEQID-02646 0.02 0.050.05 0.06 0.05 0.00 0.03 0.10 −16.61 0.56 0.01 8.30 0.53 0.71 0.00 0.23SEQID-02647 0.05 0.06 0.04 0.06 0.05 0.02 0.09 0.06 −17.98 0.57 −0.035.23 0.00 0.31 0.00 0.22 SEQID-02648 0.02 0.09 0.04 0.07 0.04 0.01 0.020.08 −16.79 0.55 −0.02 6.09 0.71 0.81 0.00 1.00 SEQID-02649 0.01 0.080.04 0.04 0.03 0.02 0.03 0.06 −23.65 0.39 0.00 6.74 0.24 0.31 0.00 0.21SEQID-02650 0.05 0.04 0.05 0.05 0.05 0.02 0.03 0.07 −19.93 0.36 0.006.72 0.21 0.35 0.19 0.21 SEQID-02651 0.04 0.07 0.05 0.04 0.05 0.01 0.030.03 −18.84 0.50 0.01 8.22 0.45 0.68 0.00 0.21 SEQID-02652 0.03 0.090.03 0.05 0.05 0.01 0.06 0.07 −12.69 0.92 0.02 9.25 0.21 0.33 0.00 0.22SEQID-02653 0.04 0.06 0.05 0.05 0.06 0.01 0.04 0.08 −18.81 0.43 0.007.37 0.21 0.33 0.21 0.21 SEQID-02654 0.03 0.06 0.04 0.04 0.05 0.05 0.050.07 −23.42 0.31 0.00 7.06 0.20 0.33 0.20 0.21 SEQID-02655 0.02 0.030.04 0.06 0.04 0.02 0.02 0.06 −19.52 0.47 −0.03 4.96 0.21 0.33 0.00 0.22SEQID-02656 0.03 0.04 0.06 0.06 0.05 0.03 0.09 0.06 −19.16 0.38 0.039.42 0.22 0.37 0.21 0.22 SEQID-02657 0.03 0.05 0.04 0.04 0.04 0.02 0.040.09 −20.62 0.40 −0.02 5.39 0.21 0.33 0.21 0.22 SEQID-02658 0.03 0.040.05 0.06 0.04 0.03 0.02 0.07 −18.73 0.55 0.02 9.11 0.20 0.33 0.00 0.22SEQID-02659 0.02 0.05 0.05 0.05 0.04 0.02 0.05 0.08 −16.18 0.54 −0.025.61 0.21 0.31 0.19 0.22 SEQID-02660 0.03 0.04 0.04 0.05 0.02 0.02 0.090.08 −19.63 0.60 −0.04 4.66 0.20 0.34 0.00 0.22 SEQID-02661 0.03 0.040.03 0.05 0.04 0.01 0.09 0.06 −23.81 0.34 0.00 6.56 0.20 0.36 0.38 0.21SEQID-02662 0.04 0.04 0.06 0.02 0.06 0.02 0.00 0.07 −23.42 0.38 −0.084.21 0.28 0.36 0.28 0.31 SEQID-02663 0.01 0.00 0.04 0.09 0.05 0.00 0.030.09 −9.95 0.75 0.08 9.58 0.71 0.80 0.28 0.28 SEQID-02664 0.02 0.02 0.020.02 0.06 0.01 0.02 0.07 −30.26 0.19 0.08 10.61 0.23 0.30 0.00 0.23SEQID-02665 0.02 0.04 0.01 0.04 0.04 0.01 0.06 0.08 −26.30 0.32 0.0610.16 0.30 0.34 0.24 0.00 SEQID-02666 0.05 0.04 0.03 0.05 0.06 0.01 0.030.08 −13.01 0.91 0.03 10.18 0.59 0.80 0.29 0.23 SEQID-02667 0.02 0.060.03 0.06 0.03 0.04 0.03 0.08 −18.21 0.45 0.05 10.66 0.52 0.63 0.26 0.00SEQID-02668 0.03 0.04 0.04 0.05 0.09 0.00 0.02 0.06 −23.27 0.33 0.0811.13 0.23 0.30 0.18 0.23 SEQID-02669 0.02 0.06 0.04 0.02 0.06 0.05 0.060.07 −15.40 0.43 −0.01 6.65 0.26 0.30 0.26 0.26 SEQID-02670 0.04 0.100.04 0.05 0.06 0.01 0.03 0.09 −17.99 0.40 0.02 8.49 0.82 0.85 0.00 0.24SEQID-02671 0.03 0.05 0.01 0.03 0.07 0.01 0.03 0.08 −22.31 0.39 0.0510.24 0.22 0.31 0.00 0.21 SEQID-02672 0.03 0.03 0.03 0.05 0.04 0.01 0.040.06 −21.21 0.39 0.05 10.27 0.00 0.30 0.00 0.18 SEQID-02673 0.02 0.060.02 0.05 0.07 0.02 0.04 0.03 −22.00 0.39 0.01 8.44 0.23 0.30 0.16 0.23SEQID-02674 0.06 0.03 0.0

0.05 0.03 0.03 0.01 0.10 −24.56 0.35 0.00 7.53 0.00 0.45 0.22 0.24SEQID-02675 0.03 0.06 0.06 0.03 0.05 0.04 0.05 0.08 −10.14 0.90 0.018.79 0.32 0.33 0.00 0.25 SEQID-02676 0.00 0.04 0.06 0.02 0.02 0.02 0.080.10 −19.85 0.53 −0.03 5.34 0.50 0.79 0.20 0.24 SEQID-02677 0.02 0.050.04 0.03 0.05 0.01 0.04 0.06 −22.73 0.36 0.10 10.80 0.20 0.31 0.00 0.00SEQID-02678 0.03 0.06 0.06 0.05 0.05 0.03 0.06 0.05 −20.62 0.36 0.028.92 0.20 0.31 0.00 0.20 SEQID-02679 0.02 0.06 0.02 0.06 0.04 0.01 0.020.07 −22.98 0.35 −0.05 4.65 0.20 0.33 0.00 0.23 SEQID-02680 0.01 0.060.04 0.06 0.04 0.01 0.04 0.08 −18.07 0.45 0.00 6.84 0.21 0.35 0.18 0.22SEQID-02681 0.04 0.06 0.05 0.06 0.05 0.02 0.02 0.07 −17.09 0.51 −0.016.28 0.30 0.43 0.00 0.21 SEQID-02682 0.04 0.02 0.02 0.05 0.06 0.00 0.020.08 −20.90 0.49 −0.01 5.39 0.21 0.33 0.22 0.22 SEQID-02683 0.02 0.030.03 0.07 0.05 0.00 0.01 0.09 −20.47 0.54 −0.02 5.11 0.21 0.33 0.20 0.22SEQID-02684 0.01 0.04 0.07 0.03 0.03 0.04 0.04 0.05 −28.42 0.38 −0.074.45 0.43 0.73 0.19 0.21 SEQID-02685 0.02 0.03 0.05 0.05 0.05 0.00 0.020.10 −17.41 0.58 0.00 7.33 0.21 0.35 0.22 0.21 SEQID-02686 0.03 0.040.04 0.06 0.05 0.01 0.05 0.07 −17.37 0.46 0.00 7.27 0.20 0.35 0.00 0.22SEQID-02687 0.02 0.04 0.03 0.07 0.04 0.02 0.05 0.05 −28.42 0.24 −0.054.61 0.44 0.69 0.00 0.20 SEQID-02688 0.02 0.07 0.04 0.07 0.05 0.02 0.040.05 −22.43 0.31 −0.01 5.79 0.19 0.55 0.00 0.20 SEQID-02689 0.03 0.050.03 0.07 0.04 0.02 0.04 0.07 −22.87 0.32 −0.05 4.72 0.18 0.33 0.19 0.19SEQID-02690 0.04 0.03 0.04 0.05 0.04 0.00 0.03 0.10 −9.31 0.92 0.08 9.060.32 0.32 0.29 0.30 SEQID-02691 0.02 0.05 0.05 0.06 0.05 0.02 0.08 0.11−18.79 0.43 −0.02 5.65 0.26 0.33 0.20 0.00 SEQID-02692 0.04 0.07 0.020.05 0.03 0.01 0.04 0.10 −21.68 0.56 0.07 10.55 0.00 0.30 0.23 0.26SEQID-02693 0.02 0.05 0.04 0.05 0.07 0.00 0.03 0.07 −10.89 0.88 0.0310.62 0.47 0.64 0.26 0.22 SEQID-02694 0.02 0.02 0.02 0.06 0.04 0.01 0.030.11 −27.06 0.27 0.15 11.62 0.22 0.30 0.17 0.22 SEQID-02695 0.03 0.010.05 0.05 0.05 0.01 0.00 0.11 −23.24 0.48 0.03 9.90 0.21 0.31 0.00 0.21SEQID-02696 0.03 0.04 0.03 0.06 0.06 0.00 0.03 0.07 −23.44 0.37 −0.035.87 0.00 0.30 0.00 0.25 SEQID-02697 0.04 0.01 0.02 0.05 0.03 0.03 0.040.08 −20.38 0.49 0.00 6.79 0.00 0.31 0.23 0.25 SEQID-02698 0.03 0.050.01 0.06 0.03 0.01 0.06 0.08 −23.35 0.29 0.08 10.48 0.00 0.33 0.00 0.23SEQID-02699 0.04 0.08 0.04 0.02 0.07 0.03 0.08 0.04 −22.58 0.23 0.1611.08 0.22 0.28 0.00 0.00 SEQID-02700 0.02 0.05 0.04 0.02 0.04 0.00 0.060.08 −26.58 0.31 0.07 10.37 0.22 0.30 0.00 0.26 SEQID-02701 0.02 0.050.03 0.03 0.02 0.01 0.05 0.06 −25.76 0.30 0.09 10.90 0.00 0.33 0.00 0.00SEQID-02702 0.02 0.06 0.06 0.04 0.06 0.01 0.04 0.05 −24.24 0.34 0.1010.81 0.23 0.32 0.00 0.00 SEQID-02703 0.01 0.06 0.07 0.05 0.06 0.01 0.040.08 −14.83 0.68 0.01 7.78 0.25 0.33 0.22 0.22 SEQID-02704 0.02 0.030.07 0.07 0.02 0.01 0.02 0.10 −14.35 0.60 0.01 7.83 0.24 0.34 0.21 0.23SEQID-02705 0.01 0.07 0.06 0.09 0.04 0.01 0.04 0.06 −18.24 0.49 −0.015.77 0.24 0.41 0.00 0.23 SEQID-02706 0.03 0.05 0.03 0.06 0.04 0.01 0.060.06 −20.80 0.37 −0.02 5.22 0.00 0.34 0.00 0.17 SEQID-02707 0.02 0.090.04 0.04 0.05 0.03 0.06 0.08 −10.43 0.97 0.02 8.57 0.19 0.33 0.22 0.22SEQID-02708 0.04 0.07 0.04 0.07 0.07 0.02 0.04 0.07 −11.61 0.98 0.006.52 0.00 0.34 0.20 0.22 SEQID-02709 0.04 0.07 0.05 0.03 0.05 0.01 0.020.09 −18.52 0.51 −0.01 6.63 0.24 0.32 0.00 0.20 SEQID-02710 0.04 0.070.06 0.04 0.04 0.04 0.06 0.06 −19.76 0.38 −0.01 6.06 0.21 0.33 0.00 0.22SEQID-02711 0.03 0.05 0.04 0.04 0.06 0.03 0.05 0.05 −22.74 0.35 0.006.86 0.22 0.31 0.00 0.20 SEQID-02712 0.01 0.04 0.05 0.07 0.05 0.02 0.050.07 −18.77 0.43 0.00 6.33 0.21 0.32 0.20 0.23 SEQID-02713 0.01 0.070.06 0.06 0.03 0.03 0.03 0.08 −19.54 0.47 −0.01 5.25 0.21 0.37 0.21 0.22SEQID-02714 0.04 0.05 0.04 0.05 0.06 0.00 0.08 0.07 −20.73 0.39 −0.025.64 0.21 0.32 0.00 0.22 SEQID-02715 0.02 0.04 0.05 0.05 0.04 0.04 0.060.06 −18.43 0.36 −0.02 6.00 0.22 0.33 0.00 0.23 SEQID-02716 0.03 0.060.04 0.06 0.04 0.02 0.04 0.06 −19.43 0.47 0.00 7.43 0.21 0.33 0.00 0.22SEQID-02717 0.02 0.05 0.06 0.06 0.05 0.03 0.04 0.06 −17.83 0.44 0.006.87 0.21 0.34 0.00 0.22 SEQID-02718 0.03 0.07 0.0G 0.06 0.04 0.02 0.040.09 −15.17 0.68 −0.01 5.53 0.20 0.33 0.00 0.22 SEQID-02719 0.03 0.050.05 0.05 0.05 0.01 0.06 0.06 −18.34 0.42 −0.01 6.38 0.21 0.33 0.00 0.22SEQID-02720 0.03 0.06 0.04 0.06 0.05 0.01 0.05 0.07 −17.71 0.48 0.017.76 0.21 0.35 0.21 0.22 SEQID-02721 0.03 0.04 0.07 0.04 0.05 0.02 0.040.08 −16.52 0.52 0.00 6.96 0.20 0.34 0.19 0.22 SEQID-02722 0.04 0.050.05 0.05 0.04 0.01 0.03 0.08 −17.69 0.56 0.02 9.42 0.20 0.33 0.00 0.21SEQID-02723 0.03 0.05 0.05 0.04 0.05 0.01 0.04 0.07 −23.11 0.36 −0.034.91 0.41 0.59 0.00 0.20 SEQID-02724 0.04 0.05 0.03 0.06 0.04 0.01 0.050.06 −18.16 0.55 −0.05 4.33 0.19 0.33 0.00 0.20 SEQID-02725 0.01 0.050.03 0.08 0.04 0.02 0.04 0.07 −16.41 0.39 0.00 6.82 0.38 0.65 0.00 0.21SEQID-02726 0.05 0.04 0.05 0.05 0.06 0.02 0.06 0.07 −19.70 0.45 −0.035.16 0.19 0.35 0.00 0.21 SEQID-02727 0.04 0.05 0.03 0.06 0.06 0.02 0.060.07 −16.67 0.51 0.00 6.78 0.20 0.69 0.51 0.21 SEQID-02728 0.06 0.040.05 0.05 0.05 0.02 0.06 0.06 −19.71 0.44 −0.03 5.16 0.19 0.33 0.00 0.20SEQID-02729 0.03 0.04 0.05 0.03 0.06 0.01 0.04 0.08 −21.97 0.41 0.039.64 0.21 0.35 0.20 0.22 SEQID-02730 0.03 0.05 0.03 0.06 0.06 0.02 0.060.08 −17.45 0.53 0.02 8.69 0.21 0.68 0.51 0.20 SEQID-02731 0.03 0.060.03 0.05 0.06 0.03 0.04 0.10 −20.31 0.50 0.01 8.19 0.284 0.94 0.22 0.00SEQID-02732 0.04 0.04 0.04 0.04 0.07 0.02 0.04 0.07 −19.63 0.47 −0.025.66 0.20 0.31 0.00 0.22 SEQID-02733 0.02 0.05 0.03 0.07 0.06 0.02 0.040.08 −19.85 0.43 0.02 3.30 0.21 0.68 0.46 0.20 SEQID-02734 0.04 0.050.03 0.05 0.06 0.03 0.04 0.10 −19.88 0.45 0.01 3.72 0.84 0.91 0.00 0.21SEQID-02735 0.01 0.05 0.02 0.00 0.01 0.00 0.03 0.02 −32.67 0.27 0.007.00 0.21 0.31 0.24 0.27 SEQID-02736 0.02 0.04 0.06 0.05 0.05 0.00 0.030.05 −25.93 0.25 0.13 10.85 0.28 0.31 0.00 0.00 SEQID-02737 0.03 0.040.04 0.09 0.06 0.02 0.04 0.09 −17.54 0.44 0.01 8.66 0.59 0.88 0.22 0.21SEQID-02738 0.01 0.05 0.05 0.07 0.05 0.05 0.06 0.07 −16.83 0.38 −0.025.73 0.99 1.00 0.00 0.21 SEQID-02739 0.01 0.07 0.28 0.07 0.02 0.00 0.070.05 −10.31 0.32 0.00 6.61 0.20 0.41 0.21 0.22 SEQID-02740 0.02 0.030.04 0.05 0.06 0.01 0.05 0.07 −18.93 0.38 0.00 7.69 0.22 0.34 0.00 0.22SEQID-02741 0.02 0.06 0.06 0.06 0.06 0.01 0.06 0.06 −20.59 0.35 −0.025.81 0.21 0.33 0.00 0.20 SEQID-02742 0.03 0.04 0.04 0.07 0.03 0.01 0.060.05 −19.66 0.44 0.00 6.93 0.20 0.32 0.00 0.22 SEQID-02743 0.03 0.060.04 0.05 0.05 0.02 0.05 0.08 −18.64 0.49 0.00 6.93 0.21 0.33 0.00 0.21SEQID-02744 0.01 0.05 0.22 0.09 0.06 0.01 0.07 0.04 −13.87 0.30 0.028.68 0.21 0.45 0.24 0.22 SEQID-02745 0.05 0.05 0.04 0.04 0.05 0.02 0.040.08 −21.23 0.37 −0.01 6.06 0.19 0.35 0.00 0.21 SEQID-02746 0.01 0.050.05 0.05 0.04 0.04 0.06 0.06 −20.01 0.36 −0.01 6.46 0.19 0.35 0.00 0.20SEQID-02747 0.06 0.12 0.03 0.06 0.06 0.00 0.00 0.05 −19.01 0.53 0.088.81 0.30 0.29 0.30 0.28 SEQID-02748 0.07 0.06 0.05 0.05 0.09 0.00 0.030.04 −15.35 0.71 0.01 7.73 0.26 0.28 0.25 0.26 SEQID-02749 0.01 0.040.02 0.01 0.07 0.00 0.06 0.05 −26.09 0.28 0.11 10.44 0.24 0.31 0.24 0.28SEQID-02750 0.01 0.08 0.05 0.05 0.04 0.02 0.04 0.08 −18.50 0.55 −0.034.81 0.20 0.31 0.00 0.22 SEQID-02751 0.03 0.03 0.05 0.06 0.04 0.02 0.030.10 −16.97 0.56 −0.01 6.25 0.26 0.34 0.20 0.22 SEQID-02752 0.03 0.090.05 0.06 0.04 0.02 0.05 0.04 −18.54 0.32 −0.03 4.97 0.00 0.34 0.00 0.00SEQID-02753 0.05 0.05 0.02 0.05 0.03 0.05 0.01 0.06 −24.99 0.39 −0.034.92 0.22 0.33 0.00 0.21 SEQID-02754 0.02 0.03 0.05 0.07 0.05 0.03 0.050.06 −18.14 0.38 0.01 9.15 0.23 0.35 0.00 0.22 SEQID-02755 0.03 0.050.04 0.04 0.06 0.01 0.03 0.07 −23.11 0.38 −0.03 4.88 0.70 0.93 0.20 0.21SEQID-02756 0.03 0.04 0.03 0.06 0.05 0.00 0.03 0.09 −18.71 0.49 −0.015.32 0.19 0.35 0.00 0.22 SEQID-02757 0.02 0.05 0.04 0.06 0.05 0.03 0.050.07 −19.94 0.41 −0.01 5.35 0.88 1.00 0.00 0.20 SEQID-02758 0.03 0.060.05 0.07 0.05 0.02 0.05 0.08 −17.81 0.43 0.00 6.97 0.19 0.33 0.20 0.21SEQID-02759 0.02 0.04 0.04 0.02 0.07 0.00 0.03 0.04 −24.18 0.30 0.1511.74 0.24 0.30 0.00 0.26 SEQID-02760 0.03 0.04 0.05 0.04 0.05 0.03 0.040.06 −16.13 0.48 0.02 9.09 0.20 0.33 0.20 0.19 SEQID-02761 0.02 0.080.04 0.07 0.05 0.03 0.05 0.04 −16.70 0.36 0.05 9.16 0.22 0.32 0.00 0.21SEQID-02762 0.02 0.07 0.07 0.07 0.04 0.04 0.06 0.03 −14.12 0.35 0.028.29 0.70 0.35 0.21 0.23 SEQID-02763 0.03 0.06 0.01 0.07 0.06 0.00 0.030.07 −15.16 0.53 −0.02 4.73 0.00 0.32 0.00 0.21 SEQID-02764 0.03 0.040.05 0.07 0.05 0.03 0.05 0.09 −16.89 0.42 0.01 8.17 0.21 0.34 0.00 0.20SEQID-02765 0.03 0.05 0.04 0.05 0.04 0.01 0.03 0.09 −19.66 0.54 −0.015.85 0.23 0.33 0.23 0.21 SEQID-02766 0.02 0.06 0.03 0.03 0.06 0.02 0.050.07 −24.03 0.34 0.13 10.76 0.67 0.75 0.21 0.22 SEQID-02767 0.04 0.070.03 0.04 0.05 0.01 0.04 0.07 −21.28 0.43 −0.01 5.55 0.22 0.33 0.00 0.20SEQID-02768 0.02 0.04 0.03 0.05 0.04 0.02 0.05 0.09 −20.12 0.41 −0.015.75 0.39 0.95 0.22 0.23 SEQID-02769 0.02 0.04 0.03 0.03 0.06 0.01 0.030.07 −24.92 0.41 −0.03 4.83 0.91 0.99 0.00 0.21 SEQID-02770 0.03 0.050.02 0.05 0.04 0.01 0.05 0.05 −28.29 0.30 −0.04 4.75 0.68 0.33 0.00 0.20SEQID-02771 0.03 0.07 0.04 0.06 0.03 0.03 0.07 0.06 −21.30 0.29 −0.026.00 0.19 0.32 0.00 0.20 SEQID-02772 0.09 0.09 0.03 0.06 0.06 0.00 0.000.05 −18.31 0.55 0.07 8.61 0.31 0.29 0.34 0.30 SEQID-02773 0.02 0.040.00 0.04 0.03 0.02 0.09 0.03 −19.07 0.13 −0.01 5.32 0.31 0.54 0.28 0.32SEQID-02774 0.01 0.04 0.03 0.05 0.05 0.03 0.03 0.05 −21.86 0.45 −0.026.41 0.36 0.44 0.23 0.20 SEQID-02775 0.02 0.05 0.02 0.05 0.06 0.00 0.060.09 −21.70 0.35 −0.03 5.54 0.74 0.89 0.24 0.22 SEQID-02776 0.02 0.070.03 0.08 0.07 0.04 0.07 0.06 −16.91 0.43 0.00 5.77 0.26 0.32 0.00 0.22SEQID-02777 0.03 0.05 0.02 0.03 0.03 0.01 0.05 0.06 −26.92 0.30 0.0910.85 0.22 0.32 0.00 0.21 SEQID-02778 0.01 0.02 0.03 0.04 0.04 0.04 0.080.07 −24.90 0.20 0.20 12.00 0.22 0.31 0.20 0.22 SEQID-02779 0.04 0.020.04 0.04 0.02 0.02 0.03 0.04 −29.48 0.17 0.22 12.05 0.00 0.30 0.22 0.24SEQID-02780 0.02 0.08 0.08 0.04 0.09 0.03 0.06 0.04 −13.34 0.33 0.027.96 1.00 1.00 0.22 0.50 SEQID-02781 0.03 0.03 0.02 0.06 0.04 0.01 0.070.04 −24.89 0.32 −0.06 4.37 0.21 0.34 0.21 0.00 SEQID-02782 0.02 0.020.11 0.05 0.05 0.00 0.02 0.08 −25.13 0.22 0.20 11.32 0.24 0.38 0.24 0.25SEQID-02783 0.01 0.02 0.12 0.04 0.06 0.00 0.01 0.06 −24.43 0.15 0.2211.47 0.29 0.43 0.25 0.29 SEQID-02784 0.04 0.09 0.05 0.04 0.05 0.03 0.050.06 −12.46 0.86 0.01 8.31 0.21 0.34 0.24 0.20 SEQID-02785 0.02 0.090.04 0.03 0.05 0.03 0.07 0.09 −11.82 0.99 0.01 8.30 0.22 0.34 0.00 0.00SEQID-02786 0.04 0.05 0.05 0.03 0.04 0.01 0.02 0.09 −18.30 0.52 −0.016.24 0.25 0.33 0.00 0.23 SEQID-02787 0.03 0.06 0.04 0.04 0.05 0.01 0.030.10 −18.28 0.54 −0.01 6.43 0.26 0.35 0.00 0.22 SEQID-02788 0.03 0.050.05 0.07 0.04 0.02 0.06 0.08 −17.31 0.52 0.00 6.63 0.21 0.33 0.00 0.21SEQID-02789 0.03 0.06 0.02 0.04 0.06 0.03 0.05 0.05 −22.14 0.37 0.006.79 0.22 0.34 0.17 0.21 SEQID-02790 0.02 0.05 0.05 0.06 0.05 0.01 0.090.08 −19.53 0.41 −0.01 6.03 0.21 0.33 0.00 0.21 SEQID-02791 0.01 0.060.04 0.06 0.05 0.02 0.04 0.08 −16.02 0.52 −0.01 6.30 0.20 0.32 0.19 0.21SEQID-02792 0.01 0.05 0.07 0.04 0.07 0.02 0.04 0.09 −25.79 0.30 −0.074.36 0.20 0.41 0.18 0.22 SEQID-02793 0.04 0.06 0.05 0.05 0.05 0.02 0.060.07 −19.92 0.39 −0.02 5.10 0.20 0.36 0.00 0.22 SEQID-02794 0.02 0.020.03 0.04 0.04 0.01 0.03 0.07 −24.57 0.38 −0.01 6.02 0.23 0.38 0.38 0.21SEQID-02795 0.05 0.06 0.05 0.06 0.05 0.02 0.05 0.06 −18.56 0.53 −0.016.68 0.21 0.33 0.00 0.23 SEQID-02796 0.05 0.04 0.05 0.05 0.06 0.02 0.060.06 −19.72 0.44 −0.03 5.17 0.20 0.34 0.00 0.20 SEQID-02797 0.05 0.040.05 0.05 0.06 0.02 0.06 0.06 −19.74 0.43 −0.03 5.16 0.21 0.31 0.00 0.21SEQID-02798 0.03 0.04 0.03 0.05 0.04 0.02 0.04 0.0

−20.29 0.44 0.00 6.53 0.91 1.00 0.22 0.22 SEQID-02799 0.03 0.05 0.040.04 0.04 0.02 0.05 0.0

−21.22 0.38 −0.02 5.73 0.21 0.33 0.20 0.22 SEQID-02800 0.05 0.05 0.040.04 0.05 0.02 0.04 0.0

−21.15 0.39 −0.01 5.97 0.19 0.33 0.00 0.21 SEQID-02801 0.02 0.04 0.030.04 0.04 0.02 0.05 0.08 −19.95 0.44 −0.01 5.53 0.89 0.99 0.20 0.22SEQID-02802 0.03 0.05 0.04 0.05 0.05 0.03 0.09 0.07 −18.37 0.70 −0.025.50 0.19 0.33 0.00 0.20 SEQID-02803 0.04 0.04 0.04 0.04 0.06 0.02 0.040.07 −19.89 0.48 −0.01 6.30 0.21 0.33 0.21 0.21 SEQID-02804 0.03 0.040.03 0.04 0.06 0.01 0.0

0.06 −22.76 0.37 −0.03 4.91 0.71 0.91 0.21 0.20 SEQID-02805 0.02 0.030.04 0.03 0.06 0.01 0.06 0.07 −19.40 0.41 0.01 8.03 0.23 0.34 0.00 0.22SEQID-02806 0.02 0.05 0.04 0.06 0.04 0.01 0.03 0.09 −20.35 0.54 0.006.70 0.24 0.33 0.20 0.21 SEQID-02807 0.03 0.05 0.05 0.04 0.06 0.01 0.040.0

−22.17 0.41 0.03 9.53 0.22 0.33 0.21 0.21 SEQID-02808 0.03 0.07 0.040.05 0.05 0.01 0.02 0.09 −19.02 0.51 −0.01 6.35 0.25 0.34 0.00 0.20SEQID-02809 0.03 0.05 0.04 0.04 0.06 0.01 0.03 0.07 −22.81 0.37 −0.024.91 0.71 0.91 0.00 0.21 SEQID-02810 0.03 0.05 0.03 0.07 0.06 0.03 0.040.10 −20.69 0.47 0.00 7.21 0.86 0.93 0.00 0.19 SEQID-02811 0.03 0.040.04 0.06 0.04 0.03 0.04 0.06 −21.89 0.38 −0.01 6.31 0.19 0.33 0.20 0.19SEQID-02812 0.03 0.06 0.04 0.05 0.04 0.02 0.06 0.06 −20.34 0.41 −0.026.02 0.19 0.35 0.00 0.21 SEQID-02813 0.01 0.03 0.07 0.05 0.04 0.00 0.010.05 −38.34 0.12 −0.07 4.92 0.28 0.45 0.13 0.26 SEQID-02814 0.03 0.060.03 0.05 0.06 0.03 0.04 0.10 −20.33 0.49 0.01 8.08 0.84 0.94 0.19 0.22SEQID-02815 0.03 0.07 0.04 0.07 0.04 0.02 0.05 0.06 −19.57 0.42 0.006.53 0.20 0.34 0.00 0.21 SEQID-02816 0.03 0.06 0.05 0.04 0.04 0.03 0.050.05 −22.17 0.35 −0.03 5.57 0.12 0.32 0.00 0.20 SEQID-02817 0.04 0.070.03 0.04 0.05 0.01 0.05 0.08 −21.34 0.43 −0.02 5.22 0.21 0.33 0.00 0.20SEQID-02818 0.02 0.05 0.04 0.05 0.04 0.01 0.06 0.06 −19.05 0.50 0.006.68 0.20 0.32 0.20 0.21 SEQID-02819 0.01 0.05 0.09 0.03 0.05 0.02 0.030.09 −25.75 0.35 −0.07 4.40 0.20 0.48 0.19 0.21 SEQID-02820 0.02 0.050.04 0.05 0.04 0.00 0.03 0.06 −24.83 0.35 −0.03 4.89 0.20 0.34 0.00 0.21SEQID-02821 0.01 0.03 0.01 0.03 0.07 0.02 0.05 0.04 −24.60 0.40 0.017.68 0.23 0.31 0.00 0.00 SEQID-02822 0.03 0.04 0.04 0.06 0.03 0.00 0.050.07 −18.84 0.46 0.00 7.93 0.22 0.32 0.00 0.22 SEQID-02823 0.02 0.080.04 0.06 0.03 0.03 0.05 0.06 −24.66 0.39 −0.05 4.72 0.20 0.32 0.00 0.23SEQID-02824 0.03 0.06 0.05 0.07 0.05 0.02 0.05 0.07 −17.72 0.41 0.007.12 0.18 0.38 0.20 0.21 SEQID-02825 0.03 0.06 0.04 0.04 0.04 0.01 0.050.07 −19.88 0.46 −0.02 5.18 0.19 0.36 0.18 0.19 SEQID-02826 0.05 0.000.00 0.00 0.02 0.00 0.06 0.00 −27.63 0.13 0.00 6.97 0.43 0.28 0.33 0.36SEQID-02827 0.03 0.07 0.03 0.03 0.04 0.04 0.00 0.13 −23.66 0.49 −0.044.98 0.56 0.68 0.00 0.00 SEQID-02828 0.02 0.07 0.07 0.04 0.04 0.01 0.040.04 −22.83 0.33 −0.02 5.93 0.24 0.35 0.20 0.23 SEQID-02829 0.03 0.060.06 0.06 0.04 0.03 0.05 0.07 −17.67 0.51 −0.01 5.99 0.22 0.33 0.00 0.23SEQID-02830 0.01 0.06 0.03 0.03 0.04 0.02 0.07 0.08 −20.80 0.48 0.006.69 0.22 0.33 0.00 0.22 SEQID-02831 0.01 0.05 0.05 0.05 0.04 0.01 0.030.09 −19.87 0.44 0.00 8.05 0.21 0.33 0.00 0.22 SEQID-02832 0.02 0.040.04 0.06 0.05 0.03 0.05 0.06 −18.85 0.43 0.00 7.06 0.20 0.35 0.00 0.21SEQID-02833 0.03 0.05 0.04 0.06 0.05 0.02 0.05 0.07 −20.31 0.41 −0.016.47 0.87 0.98 0.00 0.20 SEQID-02834 0.04 0.05 0.05 0.06 0.05 0.02 0.050.03 −18.23 0.43 0.00 6.85 0.20 0.34 0.00 0.21 SEQID-02835 0.01 0.050.04 0.05 0.04 0.04 0.02 0.12 −17.44 0.54 0.00 6.77 0.79 0.86 0.23 0.23SEQID-02836 0.00 0.02 0.10 0.09 0.01 0.00 0.19 0.01 −27.00 0.03 −0.084.40 0.25 0.38 0.21 0.26 SEQID-02837 0.03 0.05 0.04 0.09 0.07 0.02 0.040.09 −17.36 0.45 0.02 8.78 0.57 0.89 0.21 0.22 SEQID-02838 0.02 0.040.02 0.03 0.09 0.00 0.02 0.05 −23.65 0.34 0.00 7.88 0.22 0.31 0.23 0.21SEQID-02839 0.03 0.05 0.02 0.06 0.03 0.03 0.05 0.06 −20.86 0.43 0.007.03 0.22 0.35 0.22 0.21 SEQID-02840 0.02 0.05 0.05 0.06 0.05 0.02 0.050.08 −15.77 0.52 −0.01 6.24 0.22 0.33 0.00 0.21 SEQID-02841 0.03 0.060.04 0.04 0.05 0.03 0.04 0.07 −18.06 0.42 −0.02 5.81 0.19 0.32 0.00 0.20SEQID-02842 0.02 0.07 0.05 0.07 0.05 0.02 0.04 0.06 −22.46 0.30 −0.016.38 0.20 0.58 0.00 0.21 SEQID-02843 0.02 0.07 0.04 0.07 0.03 0.05 0.030.07 −19.11 0.43 0.00 7.78 0.25 0.33 0.00 0.21 SEQID-02844 0.04 0.100.04 0.07 0.07 0.01 0.02 0.08 −16.02 0.43 0.03 8.97 0.91 0.96 0.00 0.27SEQID-02845 0.04 0.10 0.04 0.05 0.07 0.01 0.02 0.08 −18.91 0.35 0.017.97 0.88 0.94 0.00 0.27 SEQID-02846 0.01 0.00 0.12 0.02 0.08 0.00 0.000.11 −32.61 0.13 −0.25 3.61 0.42 0.48 0.26 0.28 SEQID-02847 0.01 0.080.04 0.07 0.03 0.01 0.06 0.05 −20.86 0.34 0.00 7.29 0.22 0.31 0.00 0.23SEQID-02848 0.05 0.02 0.04 0.05 0.06 0.01 0.02 0.08 −19.41 0.56 0.007.59 0.21 0.33 0.00 0.21 SEQID-02849 0.03 0.05 0.04 0.04 0.05 0.03 0.050.07 −21.14 0.40 −0.01 6.25 0.20 0.31 0.00 0.22 SEQID-02850 0.04 0.030.02 0.07 0.03 0.01 0.06 0.03 −25.82 0.32 −0.07 4.40 0.22 0.33 0.19 0.00SEQID-02851 0.01 0.07 0.05 0.02 0.05 0.02 0.07 0.05 −20.48 0.38 0.049.21 0.21 0.34 0.00 0.00 SEQID-02852 0.03 0.02 0.04 0.05 0.04 0.03 0.030.10 −16.82 0.56 0.00 6.62 0.25 0.33 0.00 0.21 SEQID-02853 0.02 0.040.05 0.07 0.05 0.03 0.05 0.06 −17.53 0.38 0.01 8.99 0.22 0.35 0.00 0.23SEQID-02854 0.03 0.05 0.05 0.05 0.05 0.02 0.06 0.06 −17.07 0.49 0.007.38 0.22 0.35 0.00 0.22 SEQID-02855 0.06 0.06 0.04 0.06 0.05 0.02 0.060.06 −19.18 0.33 −0.05 4.51 0.40 0.53 0.22 0.23 SEQID-02856 0.06 0.070.03 0.05 0.05 0.02 0.05 0.06 −19.74 0.35 −0.05 4.49 0.40 0.54 0.00 0.21SEQID-02857 0.03 0.07 0.04 0.06 0.04 0.02 0.05 0.06 −19.73 0.45 −0.025.50 0.21 0.32 0.00 0.22 SEQID-02858 0.02 0.07 0.04 0.07 0.03 0.01 0.050.07 −19.33 0.50 −0.02 5.62 0.21 0.34 0.19 0.22 SEQID-02859 0.03 0.050.05 0.05 0.06 0.05 0.07 0.07 −17.75 0.42 −0.07 4.19 0.

8 0.88 0.00 0.21 SEQID-02860 0.01 0.05 0.05 0.05 0.05 0.02 0.05 0.08−16.60 0.51 −0.02 5.87 0.21 0.32 0.17 0.21 SEQID-02861 0.02 0.04 0.030.04 0.06 0.01 0.03 0.07 −24.91 0.41 −0.03 4.78 0.90 1.00 0.00 0.21SEQID-02862 0.02 0.06 0.04 0.05 0.04 0.03 0.07 0.07 −20.75 0.43 0.007.12 0.20 0.34 0.00 0.21 SEQID-02863 0.04 0.09 0.03 0.07 0.06 0.02 0.040.09 −12.26 0.95 −0.01 5.12 0.20 0.34 0.18 0.30 SEQID-02864 0.03 0.040.04 0.04 0.04 0.02 0.05 0.05 −22.85 0.36 −0.01 6.07 0.20 0.32 0.00 0.21SEQID-02865 0.02 0.05 0.00 0.09 0.02 0.02 0.0

0.02 −18.40 0.16 0.00 6.75 0.31 0.49 0.29 0.32 SEQID-02866 0.02 0.060.05 0.04 0.06 0.00 0.06 0.09 −21.29 0.39 −0.02 6.39 0.62 0.68 0.00 0.25SEQID-02867 0.02 0.03 0.04 0.05 0.04 0.03 0.02 0.09 −19.69 0.49 0.006.52 0.26 0.33 0.00 0.25 SEQID-02868 0.03 0.06 0.04 0.03 0.02 0.04 0.070.05 −26.81 0.28 −0.06 4.66 0.21 0.31 0.00 0.24 SEQID-02869 0.02 0.020.06 0.09 0.06 0.03 0.02 0.07 −14.19 0.47 −0.03 4.73 0.66 0.89 0.24 0.24SEQID-02870 0.04 0.03 0.02 0.07 0.05 0.02 0.07 0.05 −23.48 0.40 −0.064.51 0.23 0.34 0.21 0.00 SEQID-02871 0.03 0.09 0.04 0.04 0.06 0.03 0.050.06 −12.89 0.89 0.01 8.58 0.20 0.33 0.23 0.23 SEQID-02872 0.02 0.040.06 0.04 0.05 0.05 0.07 0.05 −19.05 0.32 −0.02 5.27 0.22 0.34 0.00 0.34SEQID-02873 0.02 0.07 0.05 0.06 0.05 0.02 0.06 0.03 −16.01 0.52 −0.015.46 0.28 0.41 0.00 0.23 SEQID-02874 0.05 0.05 0.05 0.04 0.03 0.01 0.020.11 −18.46 0.52 −0.01 6.41 0.25 0.33 0.00 0.25 SEQID-02875 0.05 0.050.04 0.05 0.05 0.02 0.05 0.0

−21.45 0.46 −0.0

5.01 0.00 0.30 0.00 0.19 SEQID-02876 0.04 0.03 0.05 0.05 0.03 0.03 0.040.07 −21.33 0.34 0.10 11.11 0.22 0.36 0.00 0.22 SEQID-02877 0.03 0.070.05 0.07 0.05 0.02 0.06 0.06 −20.45 0.39 0.01 7.72 0.22 0.33 0.23 0.22SEQID-02878 0.02 0.08 0.07 0.05 0.04 0.0

0.06 0.05 −20.84 0.28 0.01 7.39 0.39 0.59 0.00 0.21 SEQID-02879 0.020.09 0.06 0.04 0.04 0.02 0.06 0.06 −21.17 0.28 0.00 7.21 0.39 0.61 0.000.21 SEQID-02880 0.03 0.07 0.04 0.06 0.04 0.02 0.03 0.09 −21.19 0.530.00 7.50 0.20 0.34 0.00 0.22 SEQID-02881 0.02 0.04 0.05 0.06 0.06 0.000.03 0.09 −18.04 0.48 −0.01 6.31 0.21 0.33 0.00 0.22 SEQID-02882 0.030.04 0.10 0.10 0.04 0.00 0.05 0.05 −14.55 0.27 −0.02 5.91 0.22 0.49 0.190.21 SEQID-02883 0.05 0.05 0.05 0.07 0.05 0.03 0.04 0.08 −13.95 0.84−0.03 4.60 0.19 0.36 0.00 0.21 SEQID-02884 0.03 0.05 0.05 0.05 0.05 0.010.03 0.08 −22.71 0.37 −0.03 4.87 0.39 0.60 0.00 0.20 SEQID-02885 0.040.04 0.06 0.06 0.04 0.01 0.06 0.03 −19.93 0.30 −0.01 6.37 0.19 0.40 0.000.21 SEQID-02886 0.02 0.09 0.03 0.03 0.04 0.02 0.06 0.07 −24.09 0.38−0.08 4.23 0.38 0.43 0.21 0.25 SEQID-02887 0.03 0.07 0.06 0.06 0.06 0.010.03 0.10 −14.57 0.56 0.01 8.69 0.31 0.40 0.00 0.26 SEQID-02888 0.010.06 0.05 0.05 0.06 0.01 0.02 0.07 −28.50 0.34 −0.06 4.50 0.00 0.38 0.000.27 SEQID-02889 0.05 0.02 0.03 0.05 0.02 0.02 0.03 0.05 −30.76 0.150.22 11.99 0.21 0.31 0.21 0.23 SEQID-02890 0.03 0.06 0.03 0.05 0.06 0.030.03 0.13 −17.01 0.60 −0.01 6.50 0.27 0.32 0.22 0.00 SEQID-02891 0.010.10 0.05 0.07 0.04 0.01 0.04 0.08 −18.28 0.49 −0.02 5.59 0.23 0.34 0.000.24 SEQID-02892 0.02 0.05 0.04 0.03 0.06 0.02 0.09 0.09 −22.47 0.390.09 10.89 0.22 0.33 0.21 0.23 SEQID-02893 0.02 0.09 0.04 0.05 0.06 0.030.07 0.08 −11.49 0.93 0.01 8.30 0.20 0.33 0.00 0.21 SEQID-02894 0.010.06 0.05 0.06 0.05 0.01 0.05 0.03 −19.70 0.42 −0.01 6.07 0.75 0.85 0.000.00 SEQID-02895 0.01 0.03 0.05 0.05 0.05 0.03 0.05 0.05 −21.54 0.35−0.01 6.12 0.22 0.33 0.00 0.00 SEQID-02896 0.04 0.05 0.06 0.04 0.05 0.010.04 0.07 −20.51 0.34 0.00 6.96 0.19 0.33 0.00 0.

SEQID-02897 0.02 0.03 0.06 0.05 0.04 0.04 0.06 0.06 −18.54 0.42 0.006.73 0.00 0.36 0.00 0.23 SEQID-02898 0.03 0.05 0.03 0.03 0.06 0.02 0.050.07 −24.52 0.30 0.13 10.89 0.66 0.75 0.22 0.21 SEQID-02899 0.04 0.050.05 0.07 0.04 0.01 0.02 0.09 −17.42 0.63 0.00 7.36 0.22 0.34 0.00 0.22SEQID-02900 0.03 0.04 0.08 0.07 0.05 0.00 0.03 0.09 −20.10 0.43 0.029.93 0.21 0.36 0.00 0.23 SEQID-02901 0.02 0.05 0.03 0.07 0.05 0.01 0.030.09 −19.38 0.56 0.00 7.33 0.23 0.33 0.00 0.22 SEQID-02902 0.04 0.050.03 0.05 0.06 0.03 0.05 0.089 −21.33 0.44 −0.02 5.43 0.21 0.33 0.000.21 SEQID-02903 0.02 0.06 0.05 0.07 0.04 0.01 0.05 0.06 −18.75 0.41−0.02 5.54 0.21 0.35 0.00 0.21 SEQID-02904 0.03 0.03 0.14 0.09 0.04 0.010.04 0.05 −14.76 0.16 −0.01 6.40 0.22 0.46 0.20 0.23 SEQID-02905 0.030.06 0.06 0.06 0.04 0.02 0.0

0.09 −16.86 0.58 −0.01 6.30 0.21 0.33 0.00 0.22 SEQID-02906 0.02 0.050.04 0.05 0.06 0.01 0.05 0.06 −17.48 0.43 0.01 7.80 0.21 0.33 0.00 0.22SEQID-02907 0.02 0.05 0.05 0.06 0.05 0.02 0.05 0.07 −19.25 0.37 0.007.77 0.20 0.33 0.00 0.21 SEQID-02908 0.03 0.06 0.02 0.05 0.04 0.01 0.040.05 −27.98 0.32 −0.04 4.71 0.686 0.31 0.00 0.21 SEQID-02909 0.01 0.060.28 0.09 0.02 0.00 0.06 0.05 −10.68 0.33 −0.01 6.22 0.22 0.40 0.22 0.23SEQID-02910 0.01 0.01 0.06 0.07 0.05 0.00 0.00 0.13 −28.57 0.28 −0.153.96 0.20 0.36 0.00 0.22 SEQID-02911 0.04 0.04 0.04 0.06 0.04 0.02 0.030.05 −19.16 0.55 −0.05 4.51 0.19 0.33 0.20 0.20 SEQID-02912 0.01 0.050.03 0.06 0.07 0.03 0.03 0.05 −24.87 0.26 −0.06 4.92 0.34 0.41 0.22 0.22SEQID-02913 0.02 0.04 0.03 0.05 0.06 0.00 0.03 0.07 −23.29 0.37 −0.035.87 0.22 0.28 0.00 0.20 SEQID-02914 0.05 0.05 0.06 0.05 0.07 0.04 0.070.05 −17.27 0.37 0.04 9.15 0.25 0.29 0.00 0.23 SEQID-02915 0.04 0.090.04 0.06 0.07 0.02 0.02 0.07 −18.33 0.49 0.03 9.69 0.58 0.81 0.00 0.25SEQID-02916 0.02 0.04 0.05 0.05 0.03 0.02 0.01 0.06 −29.07 0.23 0.018.19 0.24 0.35 0.00 0.24 SEQID-02917 0.01 0.098 0.07 0.06 0.11 0.02 0.050.02 −14.45 0.36 −0.01 4.89 0.76 0.38 0.21 0.54 SEQID-02918 0.03 0.0

0.04 0.07 0.05 0.01 0.04 0.06 −19.39 0.45 −0.07 4.26 0.00 0.31 0.00 0.20SEQID-02919 0.02 0.02 0.03 0.07 0.05 0.02 0.05 0.09 −23.16 0.51 −0.074.38 0.37 0.57 0.00 0.00 SEQID-02920 0.01 0.07 0.02 0.12 0.03 0.00 0.110.05 −14.97 0.20 −0.03 4.47 0.26 0.49 0.26 0.27 SEQID-02921 0.04 0.060.05 0.05 0.06 0.01 0.05 0.09 −18.77 0.48 −0.04 5.01 0.19 0.31 0.00 0.22SEQID-02922 0.01 0.02 0.10 0.04 0.03 0.02 0.10 0.08 −20.10 0.34 −0.054.42 0.24 0.38 0.23 0.26 SEQID-02923 0.03 0.07 0.03 0.05 0.05 0.0

0.04 0.07 −20.52 0.39 0.00 7.13 0.22 0.31 0.00 0.31 SEQID-02924 0.010.07 0.05 0.07 0.08 0.01 0.04 0.06 −19.54 0.35 0.00 6.12 0.22 0.33 0.200.23 SEQID-02925 0.01 0.03 0.02 0.08 0.08 0.06 0.04 0.07 −19.59 0.440.01 7.81 0.21 0.33 0.00 0.00 SEQID-02926 0.03 0.03 0.04 0.06 0.04 0.030.05 0.09 −19.09 0.55 −0.01 6.17 0.21 0.31 0.00 0.19 SEQID-02927 0.040.03 0.04 0.03 0.04 0.02 0.05 0.07 −18.99 0.43 0.01 7.43 0.21 0.32 0.000.19 SEQID-02928 0.03 0.089 0.02 0.07 0.03 0.02 0.07 0.06 −16.20 0.470.06 10.25 0.22 0.31 0.00 0.21 SEQID-02929 0.02 0.07 0.05 0.06 0.03 0.030.08 0.04 −15.04 0.41 0.00 7.03 0.46 0.69 0.21 0.20 SEQID-02930 0.040.07 0.03 0.05 0.05 0.03 0.05 0.05 −20.89 0.33 −0.01 6.44 0.21 0.32 0.000.20 SEQID-02931 0.03 0.04 0.02 0.04 0.04 0.00 0.02 0.09 −20.45 0.50−0.01 5.86 0.24 0.33 0.00 0.71 SEQID-02932 0.03 0.06 0.05 0.04 0.03 0.070.04 0.05 −21.27 0.39 −0.04 4.86 0.21 0.32 0.00 0.19 SEQID-02933 0.030.06 0.04 0.06 0.06 0.03 0.07 0.05 −19.56 0.32 −0.01 5.95 0.22 0.33 0.000.20 SEQID-02934 0.02 0.05 0.03 0.06 0.05 0.00 0.04 0.05 −22.41 0.31−0.04 4.85 0.21 0.30 0.00 0.20 SEQID-02935 0.01 0.05 0.05 0.07 0.04 0.020.04 0.06 −20.31 0.35 −0.01 6.72 0.20 0.31 0.19 0.22 SEQID-02936 0.030.06 0.04 0.06 0.05 0.01 0.06 0.08 −19.63 0.38 −0.05 4.64 0.82 0.90 0.200.21 SEQID-02937 0.02 0.05 0.06 0.06 0.05 0.01 0.05 0.05 −19.29 0.30−0.01 5.88 0.19 0.31 0.18 0.20 SEQID-02938 0.04 0.06 0.04 0.08 0.04 0.010.07 0.07 −18.49 0.41 −0.01 6.29 0.21 0.33 0.21 0.22 SEQID-02939 0.020.06 0.04 0.03 0.06 0.03 0.05 0.06 −19.69 0.38 0.00 6.79 0.20 0.33 0.180.22 SEQID-02940 0.03 0.04 0.04 0.05 0.05 0.01 0.05 0.07 −18.93 0.420.00 7.40 0.21 0.34 0.19 0.21 SEQID-02941 0.03 0.05 0.03 0.04 0.05 0.030.04 0.06 −20.20 0.55 −0.02 6.29 0.20 0.34 0.19 0.21 SEQID-02942 0.020.06 0.04 0.06 0.05 0.01 0.05 0.07 −17.95 0.49 0.00 7.37 0.21 0.35 0.000.21 SEQID-02943 0.04 0.05 0.05 0.05 0.06 0.02 0.06 0.07 −19.44 0.39−0.02 5.02 0.20 0.35 0.00 0.22 SEQID-02944 0.02 0.06 0.04 0.05 0.05 0.010.05 0.07 −21.66 0.38 −0.01 6.19 0.21 0.33 0.00 0.20 SEQID-02945 0.020.05 0.06 0.08 0.06 0.03 0.04 0.07 −17.48 0.38 −0.03 4.85 0.18 0.40 0.190.19 SEQID-02946 0.01 0.01 0.00 0.07 0.04 0.00 0.01 0.05 −28.23 0.22−0.09 4.43 0.21 0.40 0.19 0.18 SEQID-02947 0.02 0.07 0.06 0.07 0.03 0.020.06 0.10 −17.49 0.42 0.01 8.20 0.29 0.36 0.21 0.25 SEQID-02948 0.050.03 0.05 0.02 0.07 0.03 0.06 0.04 −15.48 0.46 −0.05 4.33 0.90 0.94 0.250.26 SEQID-02949 0.01 0.07 0.04 0.05 0.05 0.01 0.03 0.09 −19.80 0.54−0.03 4.97 0.40 0.50 0.20 0.24 SEQID-02950 0.06 0.03 0.06 0.03 0.06 0.020.04 0.06 −20.78 0.34 −0.04 4.59 0.19 0.30 0.21 0.21 SEQID-02951 0.060.08 0.02 0.03 0.05 0.00 0.04 0.08 −17.44 0.49 0.04 9.84 0.20 0.28 0.000.21 SEQID-02952 0.04 0.05 0.03 0.05 0.04 0.01 0.08 0.07 −19.06 0.55−0.01 6.24 0.25 0.32 0.00 0.24 SEQID-02953 0.04 0.05 0.06 0.06 0.01 0.010.06 0.07 −22.91 0.40 −0.02 5.85 0.23 0.32 0.21 0.21 SEQID-02954 0.020.02 0.04 0.04 0.03 0.05 0.09 0.06 −25.46 0.19 0.21 11.95 0.21 0.31 0.000.20 SEQID-02955 0.01 0.08 0.06 0.07 0.06 0.01 0.02 0.10 −19.22 0.48−0.02 5.00 0.23 0.34 0.00 0.00 SEQID-02956 0.04 0.04 0.04 0.07 0.05 0.010.09 0.05 −17.31 0.47 0.00 7.36 0.19 0.30 0.21 0.00 SEQID-02957 0.020.06 0.06 0.05 0.02 0.03 0.06 0.09 −17.40 0.53 −0.01 6.15 0.00 0.35 0.000.25 SEQID-02958 0.03 0.07 0.06 0.05 0.03 0.04 0.04 0.11 −19.49 0.49−0.03 4.99 0.20 0.33 0.00 0.24 SEQID-02959 0.04 0.07 0.04 0.04 0.01 0.050.06 0.05 −23.42 0.35 −0.02 5.65 0.54 0.65 0.20 0.22 SEQID-02960 0.020.05 0.03 0.05 0.04 0.00 0.03 0.05 −27.13 0.26 0.15 11.29 0.22 0.33 0.210.19 SEQID-02961 0.02 0.07 0.05 0.05 0.03 0.02 0.04 0.06 −21.97 0.48−0.03 4.82 0.21 0.31 0.00 0.23 SEQID-02962 0.01 0.07 0.04 0.06 0.04 0.030.03 0.06 −18.34 0.73 0.02 8.87 0.23 0.31 0.23 0.00 SEQID-02963 0.030.08 0.03 0.09 0.06 0.05 0.06 0.06 −11.63 0.39 0.03 8.62 0.29 0.37 0.000.19 SEQID-02964 0.05 0.09 0.05 0.07 0.03 0.02 0.05 0.06 −17.63 0.47−0.01 6.39 0.22 0.33 0.00 0.24 SEQID-02965 0.02 0.03 0.05 0.04 0.06 0.020.06 0.09 −19.23 0.41 −0.03 5.74 0.22 0.34 0.00 0.18 SEQID-02966 0.030.05 0.04 0.03 0.04 0.01 0.03 0.07 −27.55 0.31 0.00 6.78 0.21 0.31 0.000.20 SEQID-02967 0.01 0.05 0.01 0.04 0.04 0.02 0.06 0.04 −24.79 0.29−0.04 4.81 0.23 0.32 0.00 0.00 SEQID-02968 0.03 0.08 0.05 0.06 0.04 0.030.06 0.04 −17.45 0.36 0.00 6.84 0.21 0.34 0.00 0.00 SEQID-02969 0.020.07 0.06 0.06 0.03 0.03 0.05 0.09 −20.02 0.45 −0.04 5.20 0.22 0.33 0.000.00 SEQID-02970 0.02 0.06 0.04 0.04 0.05 0.01 0.04 0.06 −21.16 0.420.10 10.87 0.19 0.31 0.00 0.19 SEQID-02971 0.03 0.07 0.05 0.05 0.04 0.030.03 0.05 −22.23 0.31 −0.01 6.60 0.23 0.31 0.00 0.21 SEQID-02972 0.030.07 0.06 0.05 0.02 0.03 0.05 0.07 −18.72 0.44 −0.01 6.56 0.22 0.30 0.200.00 SEQID-02973 0.03 0.06 0.04 0.04 0.04 0.02 0.06 0.07 −19.70 0.48−0.02 5.27 0.19 0.31 0.00 0.21 SEQID-02974 0.02 0.07 0.06 0.05 0.07 0.030.05 0.05 −16.20 0.43 0.00 6.87 0.32 0.56 0.00 0.21 SEQID-02975 0.020.08 0.05 0.07 0.04 0.03 0.03 0.09 −17.95 0.53 −0.02 5.26 0.27 0.43 0.000.23 SEQID-02976 0.04 0.07 0.04 0.05 0.02 0.02 0.04 0.06 −22.45 0.37−0.01 6.32 0.22 0.31 0.00 0.00 SEQID-02977 0.02 0.09 0.06 0.08 0.04 0.010.03 0.03 −16.20 0.41 0.03 8.98 0.19 0.39 0.00 0.21 SEQID-02978 0.020.10 0.07 0.06 0.05 0.01 0.03 0.06 −16.32 0.50 0.01 7.98 0.22 0.31 0.000.18 SEQID-02979 0.03 0.06 0.05 0.04 0.05 0.01 0.06 0.08 −15.90 0.61−0.02 5.54 0.21 0.33 0.00 0.22 SEQID-02980 0.02 0.08 0.06 0.06 0.03 0.040.04 0.03 −19.54 0.34 −0.02 6.05 0.22 0.36 0.00 0.20 SEQID-02981 0.010.08 0.04 0.04 0.03 0.02 0.03 0.06 −23.94 0.40 −0.01 6.61 0.21 0.32 0.000.21 SEQID-02982 0.04 0.04 0.05 0.05 0.03 0.03 0.06 0.09 −17.80 0.470.00 6.52 0.22 0.32 0.00 0.22 SEQID-02983 0.02 0.06 0.04 0.03 0.06 0.020.03 0.07 −21.58 0.39 −0.02 5.91 0.22 0.33 0.00 0.20 SEQID-02984 0.030.05 0.04 0.04 0.04 0.00 0.04 0.05 −24.33 0.21 −0.01 5.95 0.22 0.33 0.000.22 SEQID-02985 0.03 0.04 0.04 0.04 0.04 0.00 0.02 0.06 −25.10 0.40−0.04 4.72 0.22 0.33 0.00 0.22 SEQID-02986 0.02 0.06 0.06 0.09 0.03 0.020.05 0.04 −19.85 0.35 0.00 7.65 0.22 0.35 0.21 0.23 SEQID-02987 0.030.07 0.02 0.05 0.05 0.01 0.04 0.05 −22.33 0.36 −0.02 5.27 0.21 0.33 0.000.21 SEQID-02988 0.03 0.07 0.06 0.04 0.03 0.03 0.05 0.06 −22.46 0.330.02 8.89 0.22 0.35 0.19 0.22 SEQID-02989 0.04 0.04 0.09 0.04 0.05 0.030.07 0.05 −14.73 0.27 −0.01 5.49 0.24 0.45 0.21 0.21 SEQID-02990 0.030.07 0.06 0.06 0.04 0.03 0.02 0.06 −21.06 0.34 −0.02 6.17 0.21 0.32 0.200.21 SEQID-02991 0.03 0.04 0.04 0.06 0.04 0.02 0.06 0.07 −20.54 0.380.00 7.00 0.22 0.33 0.20 0.21 SEQID-02992 0.04 0.05 0.05 0.06 0.04 0.010.04 0.06 −20.34 0.41 0.01 7.74 0.21 0.32 0.00 0.21 SEQID-02993 0.020.06 0.05 0.06 0.06 0.03 0.03 0.06 −14.67 0.41 0.03 9.69 0.21 0.31 0.000.22 SEQID-02994 0.03 0.04 0.04 0.09 0.05 0.02 0.02 0.09 −16.75 0.580.00 7.11 0.22 0.33 0.20 0.22 SEQID-02995 0.03 0.05 0.05 0.05 0.03 0.010.0

0.07 −19.38 0.60 −0.03 4.83 0.20 0.33 0.19 0.22 SEQID-02996 0.02 0.010.12 0.09 0.06 0.01 0.10 0.03 −11.88 0.11 −0.01 6.00 0.28 0.41 0.20 0.24SEQID-02997 0.03 0.06 0.03 0.07 0.04 0.00 0.03 0.06 −20.23 0.45 −0.016.09 0.19 0.32 0.00 0.21 SEQID-02998 0.02 0.09 0.04 0.05 0.05 0.07 0.050.04 −12.06 0.63 0.00 7.24 0.20 0.35 0.00 0.20 SEQID-02999 0.03 0.070.04 0.06 0.04 0.03 0.07 0.06 −21.11 0.31 −0.04 5.06 0.19 0.32 0.00 0.21SEQID-03000 0.04 0.03 0.07 0.10 0.04 0.00 0.01 0.06 −15.56 0.26 −0.025.67 0.22 0.37 0.19 0.22 SEQID-03001 0.02 0.07 0.03 0.06 0.04 0.03 0.050.07 −19.76 0.47 −0.03 5.03 0.19 0.32 0.00 0.20 SEQID-03002 0.03 0.050.03 0.06 0.05 0.03 0.06 0.06 −20.82 0.39 −0.04 4.80 0.19 0.33 0.00 0.20SEQID-03003 0.03 0.03 0.03 0.06 0.05 0.01 0.04 0.07 −19.78 0.57 −0.015.64 0.19 0.32 0.19 0.20 SEQID-03004 0.02 0.0

0.04 0.06 0.04 0.02 0.09 0.06 −20.40 0.42 −0.03 4.91 0.19 0.34 0.19 0.20SEQID-03005 0.02 0.07 0.04 0.04 0.04 0.02 0.07 0.06 −24.11 0.26 −0.025.83 0.19 0.34 0.13 0.19 SEQID-03006 0.01 0.08 0.04 0.06 0.03 0.01 0.090.04 −21.51 0.41 −0.01 6.63 0.56 0.74 0.19 0.22 SEQID-03007 0.01 0.070.03 0.09

0.02 0.00 0.01 0.07 −323.03 0.55 −0.01 6.35 0.50 0.91 0.00 0.22SEQID-03008 0.02 0.06 0.04 0.06 0.05 0.03 0.05 0.07 −20.05 0.43 −0.016.37 0.86 0.98 0.00 0.20 SEQID-03009 0.02 0.11 0.03 0.05 0.06 0.01 0.110.03 −20.47 0.29 0.01 8.37 0.21 0.30 0.00 0.00 SEQID-03010 0.02 0.110.05 0.06 0.03 0.01 0.02 0.03 −19.04 0.49 −0.02 5.21 0.68 0.78 0.24 0.28SEQID-03011 0.03 0.05 0.06 0.04 0.06 0.01 0.04 0.09 −21.63 0.39 0.039.63 0.22 0.35 0.00 0.22 SEQID-03012 0.05 0.04 0.05 0.06 0.05 0.02 0.060.06 −19.72 0.44 −0.03 5.16 0.20 0.33 0.00 0.19 SEQID-03013 0.02 0.060.03 0.05 0.05 0.04 0.04 0.07 −25.34 0.45 −0.06 4.56 0.22 0.30 0.23 0.22SEQID-03014 0.01 0.03 0.04 0.05 0.06 0.01 0.05 0.07 −18.24 0.43 0.006.64 0.31 0.32 0.00 0.21 SEQID-03015 0.03 0.04 0.04 0.07 0.04 0.01 0.060.06 −18.93 0.43 0.00 6.94 0.21 0.32 0.00 0.21 SEQID-03016 0.01 0.060.03 0.06 0.0

0.02 0.03 0.10 −19.58 0.53 −0.02 5.04 0.83 0.93 0.00 0.20 SEQID-030170.04 0.06 0.04 0.05 0.04 0.00 0.07 0.07 −21.13 0.44 −0.02 5.82 0.21 0.320.19 0.21 SEQID-03018 0.02 0.06 0.04 0.03 0.06 0.03 0.05 0.06 −20.230.36 −0.01 6.46 0.20 0.31 0.00 0.22 SEQID-03019 0.02 0.10 0.04 0.0

0.05 0.01 0.01 0.08 −17.15 0.29 0.03 8.90 0.92 0.96 0.25 0.29SEQID-03020 0.03 0.03 0.05 0.06 0.04 0.02 0.03 0.09 −16.97 0.56 −0.016.25 0.25 0.33 0.00 0.22 SEQID-03021 0.03 0.05 0.01 0.03 0.09 0.02 0.050.03 −22.71 0.45 0.04 8.97 0.23 0.35 0.20 0.24 SEQID-03022 0.03 0.040.03 0.06 0.04 0.01 0.06 0.04 −24.82 0.32 −0.06 4.42 0.23 0.32 0.00 0.00SEQID-03023 0.01 0.08 0.05 0.01 0.05 0.01 0.06 0.07 −20.92 0.34 0.006.86 0.20 0.34 0.00 0.00 SEQID-03024 0.02 0.04 0.02 0.04 0.10 0.00 0.010.06 −23.57 0.35 −0.01 5.90 0.23 0.30 0.24 0.00 SEQID-03025 0.03 0.040.02 0.04 0.04 0.04 0.06 0.07 −24.54 0.25 −0.02 6.43 0.34 0.45 0.26 0.22SEQID-03026 0.03 0.03 0.02 0.06 0.04 0.01 0.07 0.05 −25.35 0.27 −0.064.51 0.20 0.31 0.00 0.00 SEQID-03027 0.01 0.04 0.05 0.06 0.05 0.04 0.060.05 −19.12 0.36 −0.02 5.88 0.21 0.33 0.19 0.21 SEQID-03028 0.02 0.030.03 0.06 0.04 0.01 0.04 0.08 −21.36 0.43 0.06 10.49 0.00 0.31 0.00 0.00SEQID-03029 0.03 0.04 0.03 0.04 0.06 0.02 0.04 0.07 −19.49 0.49 −0.025.52 0.21 0.33 0.21 0.23 SEQID-03030 0.02 0.09 0.01 0.04 0.05 0.02 0.020.05 −22.57 0.60 0.00 7.12 0.34 0.32 0.33 0.29 SEQID-03031 0.01 0.060.07 0.05 0.05 0.01 0.03 0.07 −24.45 0.29 0.12 10.85 0.00 0.34 0.18 0.23SEQID-03032 0.03 0.04 0.05 0.06 0.05 0.00 0.03 0.05 −35.70 0.25 0.1310.82 0.25 0.32 0.19 0.21 SEQID-03033 0.02 0.04 0.04 0.03 0.06 0.00 0.080.09 −20.37 0.36 −0.03 5.31 0.69 0.73 0.00 0.00 SEQID-03034 0.03 0.040.08 0.03 0.05 0.04 0.03 0.05 −17.12 0.45 −0.03 4.86 0.21 0.13 0.19 0.00SEQID-03035 0.07 0.00 0.04 0.04 0.13 0.00 0.02 0.06 −20.21 0.09 0.039.81 0.25 0.34 0.27 0.24 SEQID-03036 0.04 0.03 0.03 0.03 0.04 0.01 0.030.12 −21.66 0.60 −0.02 6.08 0.21 0.29 0.00 0.22 SEQID-03037 0.04 0.050.03 0.06 0.05 0.02 0.06 0.06 −19.45 0.37 −0.01 5.34 0.22 0.33 0.00 0.20SEQID-03038 0.03 0.05 0.05 0.04 0.06 0.01 0.04 0.06 −20.55 0.32 0.017.69 0.21 0.32 0.00 0.20 SEQID-03039 0.02 0.07 0.01 0.04 0.04 0.00 0.020.03 −20.98 0.57 0.03 9.26 0.37 0.26 0.00 0.00 SEQID-03040 0.01 0.080.02 0.05 0.06 0.03 0.03 0.07 −16.75 0.76 0.02 3.49 0.91 0.95 0.21 0.24SEQID-03041 0.01 0.03 0.04 0.07 0.03 0.00 0.03 0.07 −18.61 0.39 0.0911.01 0.26 0.30 0.25 0.00 SEQID-03042 0.04 0.03 0.01 0.04 0.13 0.00 0.010.01 −25.65 0.04 0.02 9.76 0.23 0.32 0.22 0.25 SEQID-03043 0.03 0.070.06 0.06 0.04 0.04 0.06 0.09 −17.32 0.45 0.03 9.14 0.21 0.32 0.00 0.23SEQID-03044 0.01 0.06 0.04 0.05 0.05 0.04 0.10 0.03 −19.15 0.23 0.007.43 0.21 0.33 0.00 0.21 SEQID-03045 0.01 0.08 0.05 0.04 0.07 0.03 0.050.06 −20.02 0.37 −0.01 6.24 0.21 0.32 0.00 0.21 SEQID-03046 0.03 0.060.04 0.04 0.06 0.02 0.04 0.07 −23.48 0.33 0.12 10.99 0.79 0.90 0.00 0.23SEQID-03047 0.02 0.06 0.06 0.03 0.05 0.01 0.0

0.09 −16.16 0.52 0.00 6.97 0.26 0.35 0.00 0.00 SEQID-03048 0.02 0.060.02 0.06 0.07 0.02 0.04 0.09 −15.02 0.50 0.01 8.45 0.35 0.45 0.00 0.20SEQID-03049 0.02 0.05 0.03 0.05 0.07 0.01 0.03 0.09 −22.62 0.39 −0.015.23 0.57 0.81 0.00 0.21 SEQID-03050 0.03 0.06 0.04 0.04 0.06 0.01 0.040.08 −21.59 0.42 0.00 6.52 0.19 0.34 0.00 0.21 SEQID-03051 0.00 0.050.03 0.07 0.09 0.02 0.06 0.09 −17.58 0.35 0.02 9.31 0.21 0.32 0.00 0.21SEQID-03052 0.03 0.05 0.05 0.05 0.04 0.04 0.08 0.06 −20.46 0.29 0.007.34 0.20 0.31 0.00 0.00 SEQID-03053 0.03 0.04 0.04 0.06 0.05 0.01 0.040.07 −18.67 0.44 0.02 9.52 0.22 0.33 0.00 0.22 SEQID-03054 0.02 0.040.04 0.06 0.05 0.02 0.05 0.08 −19.24 0.43 −0.01 5.92 0.19 0.34 0.19 0.20SEQID-03055 0.03 0.05 0.04 0.05 0.06 0.01 0.04 0.08 −19.08 0.41 0.006.72 0.19 0.34 0.20 0.20 SEQID-03056 0.01 0.04 0.03 0.04 0.05 0.03 0.050.08 −19.53 0.43 0.01 7.61 0.00 0.34 0.00 0.21 SEQID-03057 0.01 0.050.06 0.05 0.05 0.04 0.04 0.06 −19.12 0.42 0.00 6.92 0.22 0.34 0.00 0.21SEQID-03058 0.02 0.05 0.04 0.06 0.06 0.01 0.04 0.06 −22.49 0.34 −0.034.80 0.77 0.94 0.00 0.22 SEQID-03059 0.02 0.05 0.03 0.05 0.06 0.00 0.040.07 −20.31 0.50 0.00 6.69 0.19 0.32 0.00 0.21 SEQID-03060 0.02 0.060.05 0.04 0.03 0.00 0.05 0.09 −22.21 0.35 0.02 9.07 0.00 0.31 0.00 0.20SEQID-03061 0.01 0.04 0.04 0.06 0.05 0.02 0.04 0.06 −19.15 0.39 −0.015.92 0.89 0.81 0.21 0.22 SEQID-03062 0.04 0.07 0.04 0.04 0.08 0.02 0.040.07 −16.48 0.42 0.01 7.99 0.52 0.66 0.21 0.21 SEQID-03063 0.01 0.030.04 0.03 0.06 0.01 0.05 0.08 −20.11 0.35 0.13 11.50 0.00 0.33 0.23 0.00SEQID-03064 0.02 0.06 0.04 0.05 0.05 0.02 0.05 0.06 −18.36 0.44 0.006.68 0.22 0.33 0.20 0.20 SEQID-03065 0.03 0.05 0.04 0.04 0.06 0.02 0.0

0.08 −21.98 0.43 0.03 9.72 0.21 0.35 0.20 0.21 SEQID-03066 0.02 0.090.03 0.06 0.05 0.03 0.04 0.05 −18.92 0.42 0.00 6.98 0.20 0.33 0.20 0.21SEQID-03067 0.02 0.05 0.04 0.05 0.05 0.02 0.04 0.08 −19.81 0.42 0.017.82 0.21 0.34 0.23 0.23 SEQID-03068 0.02 0.06 0.04 0.06 0.07 0.03 0.060.06 −19.97 0.37 −0.02 5.11 0.20 0.33 0.00 0.20 SEQID-03069 0.01 0.050.04 0.06 0.04 0.03 0.05 0.06 −19.66 0.39 0.00 6.90 0.19 0.35 0.19 0.20SEQID-03070 0.03 0.07 0.05 0.04 0.05 0.00 0.04 0.09 −18.54 0.56 −0.025.09 0.00 0.47 0.00 0.00 SEQID-03071 0.01 0.07 0.03 0.04 0.04 0.01 0.070.04 −28.05 0.24 0.01 8.70 0.23 0.33 0.00 0.00 SEQID-03072 0.03 0.040.03 0.05 0.05 0.02 0.05 0.11 −18.60 0.46 0.01 7.87 0.67 0.85 0.00 0.21SEQID-03073 0.03 0.06 0.05 0.05 0.06 0.02 0.05 0.06 −19.47 0.46 −0.035.16 0.21 0.31 0.00 0.22 SEQID-03074 0.02 0.05 0.04 0.05 0.05 0.03 0.050.05 −18.35 0.42 −0.01 5.93 0.21 0.34 0.22 0.22 SEQID-03075 0.02 0.080.02 0.04 0.04 0.05 0.06 0.04 −21.86 0.28 −0.01 6.47 0.20 0.32 0.00 0.21SEQID-03076 0.02 0.07 0.04 0.06 0.06 0.01 0.06 0.05 −19.88 0.35 0.005.88 0.18 0.32 0.20 0.20 SEQID-03077 0.02 0.05 0.05 0.05 0.02 0.01 0.040.07 −22.48 0.31 0.15 11.36 0.21 0.33 0.24 0.00 SEQID-03078 0.01 0.050.04 0.03 0.04 0.01 0.05 0.05 −23.11 0.29 0.10 10.88 0.19 0.34 0.23 0.18SEQID-03079 0.01 0.04 0.05 0.05 0.04 0.02 0.02 0.08 −20.31 0.40 0.1211.80 0.00 0.34 0.00 0.22 SEQID-03080 0.02 0.04 0.06 0.05 0.06 0.03 0.030.06 −19.58 0.48 0.01 8.06 0.22 0.31 0.00 0.22 SEQID-03081 0.01 0.070.05 0.05 0.04 0.03 0.06 0.06 −21.85 0.36 −0.02 5.16 0.21 0.37 0.00 0.21SEQID-03082 0.03 0.05 0.03 0.05 0.05 0.01 0.04 0.05 −21.22 0.37 0.018.03 0.20 0.34 0.00 0.21 SEQID-03083 0.02 0.07 0.05 0.05 0.05 0.03 0.060.06 −16.47 0.45 0.00 7.52 0.27 0.41 0.00 0.21 SEQID-03084 0.03 0.020.05 0.04 0.07 0.01 0.04 0.07 −18.74 0.50 −0.01 6.52 0.20 0.32 0.00 0.21SEQID-03085 0.02 0.06 0.05 0.04 0.06 0.04 0.07 0.05 −20.38 0.31 −0.035.48 0.20 0.31 0.00 0.21 SEQID-03086 0.02 0.06 0.05 0.06 0.05 0.03 0.040.07 −20.38 0.42 0.00 7.06 0.47 0.79 0.00 0.21 SEQID-03087 0.04 0.060.05 0.05 0.04 0.03 0.05 0.06 −19.20 0.47 0.01 8.45 0.21 0.29 0.26 0.00SEQID-03088 0.01 0.03 0.02 0.03 0.05 0.02 0.02 0.07 −24.99 0.26 0.1211.41 0.22 0.31 0.22 0.23 SEQID-03089 0.03 0.03 0.01 0.04 0.06 0.01 0.020.09 −23.22 0.37 0.05 10.11 0.22 0.30 0.00 0.21 SEQID-03090 0.02 0.050.04 0.04 0.03 0.01 0.07 0.06 −23.97 0.27 0.13 10.81 0.23 0.33 0.21 0.24SEQID-03091 0.04 0.02 0.02 0.06 0.06 0.01 0.06 0.05 −26.20 0.23 −0.084.33 0.24 0.33 0.18 0.20 SEQID-03092 0.02 0.05 0.06 0.02 0.05 0.01 0.0

0.07 −21.77 0.43 0.12 11.07 0.24 0.32 0.00 0.21 SEQID-03093 0.01 0.040.05 0.07 0.05 0.01 0.04 0.11 −16.57 0.61 0.01 8.40 0.50 0.78 0.22 0.22SEQID-03094 0.03 0.03 0.03 0.04 0.06 0.02 0.06 0.07 −18.75 0.45 −0.016.56 0.22 0.33 0.00 0.22 SEQID-03095 0.02 0.06 0.05 0.03 0.05 0.05 0.070.05 −19.90 0.35 −0.04 4.93 0.21 0.31 0.00 0.21 SEQID-03096 0.01 0.050.04 0.06 0.06 0.02 0.06 0.06 −16.33 0.42 0.00 6.83 0.20 0.33 0.00 0.21SEQID-03097 0.02 0.04 0.04 0.04 0.07 0.00 0.05 0.04 −24.94 0.30 0.1310.64 0.19 0.31 0.00 0.26 SEQID-03098 0.03 0.06 0.04 0.03 0.06 0.01 0.030.05 −23.63 0.37 0.09 10.91 0.19 0.33 0.00 0.23 SEQID-03099 0.01 0.030.04 0.03 0.02 0.01 0.04 0.05 −26.92 0.31 0.10 11.08 0.23 0.31 0.00 0.22SEQID-03100 0.03 0.05 0.05 0.04 0.06 0.02 0.05 0.05 −19.28 0.44 −0.016.29 0.27 0.39 0.24 0.21 SEQID-03101 0.01 0.04 0.04 0.03 0.04 0.01 0.040.06 −27.30 0.32 0.14 11.16 0.00 0.30 0.21 0.00 SEQID-03102 0.01 0.050.06 0.05 0.06 0.01 0.05 0.07 −22.87 0.31 0.09 10.73 0.20 0.31 0.24 0.00SEQID-03103 0.04 0.09 0.02 0.07 0.04 0.02 0.08 0.07 −15.74 0.53 0.0610.38 0.00 0.35 0.00 0.21 SEQID-03104 0.02 0.04 0.04 0.05 0.07 0.02 0.030.09 −21.48 0.38 0.01 8.42 0.22 0.31 0.00 0.00 SEQID-03105 0.02 0.040.05 0.04 0.06 0.02 0.05 0.09 −19.87 0.41 0.00 7.00 0.21 0.32 0.22 0.21SEQID-03106 0.01 0.05 0.05 0.05 0.07 0.01 0.04 0.07 −22.28 0.37 −0.025.36 0.54 0.74 0.00 0.20 SEQID-03107 0.02 0.07 0.05 0.05 0.05 0.03 0.050.07 −16.48 0.71 0.01 8.20 0.19 0.32 0.00 0.20 SEQID-03108 0.03 0.030.03 0.06 0.11 0.04 0.02 0.09 −11.10 0.46 0.02 9.37 0.22 0.30 0.28 0.24SEQID-03109 0.01 0.02 0.03 0.05 0.03 0.02 0.07 0.06 −28.09 0.25 −0.035.14 0.21 0.30 0.25 0.23 SEQID-03110 0.01 0.01 0.04 0.03 0.02 0.03 0.100.08 −25.01 0.16 0.21 11.85 0.23 0.33 0.00 0.23 SEQID-03111 0.02 0.050.06 0.04 0.04 0.04 0.04 0.07 −20.07 0.33 −0.01 6.71 0.22 0.30 0.00 0.20SEQID-03112 0.01 0.05 0.04 0.04 0.05 0.02 0.05 0.07 −20.65 0.42 0.006.93 0.21 0.35 0.20 0.22 SEQID-03113 0.04 0.07 0.06 0.05 0.04 0.03 0.050.05 −17.86 0.33 −0.01 6.64 0.21 0.32 0.21 0.22 SEQID-03114 0.02 0.070.04 0.05 0.05 0.02 0.07 0.06 −23.81 0.31 −0.02 5.72 0.19 0.34 0.00 0.21SEQID-03115 0.02 0.06 0.03 0.06 0.05 0.01 0.05 0.05 −26.40 0.31 −0.054.56 0.70 0.90 0.00 0.21 SEQID-03116 0.02 0.04 0.06 0.05 0.05 0.03 0.050.07 −19.40 0.39 −0.01 6.30 0.19 0.33 0.00 0.20 SEQID-03117 0.02 0.050.05 0.05 0.06 0.02 0.04 0.06 −18.78 0.43 −0.01 6.39 0.19 0.34 0.00 0.21SEQID-03118 0.01 0.07 0.04 0.05 0.05 0.06 0.05 0.07 −20.64 0.35 −0.025.83 0.20 0.33 0.00 0.20 SEQID-03119 0.03 0.11 0.02 0.05 0.08 0.01 0.030.09 −18.42 0.35 0.02 9.48 0.74 0.39 0.00 0.23 SEQID-03120 0.02 0.080.04 0.01 0.06 0.02 0.05 0.07 −20.86 0.42 0.00 7.03 0.22 0.31 0.19 0.00SEQID-03121 0.03 0.07 0.05 0.03 0.05 0.02 0.03 0.07 −20.22 0.50 0.0910.96 0.22 0.35 0.21 0.23 SEQID-03122 0.02 0.04 0.06 0.03 0.06 0.06 0.030.06 −18.08 0.50 −0.02 5.17 0.21 0.35 0.00 0.20 SEQID-03123 0.01 0.050.06 0.07 0.05 0.00 0.03 0.09 −16.57 0.58 0.01 9.02 0.64 0.76 0.25 0.21SEQID-03124 0.02 0.05 0.04 0.05 0.05 0.02 0.07 0.06 −20.22 0.36 −0.025.13 0.21 0.31 0.00 0.20 SEQID-03125 0.02 0.08 0.04 0.05 0.06 0.01 0.060.07 −18.92 0.41 0.00 7.29 0.20 0.31 0.22 0.21 SEQID-03126 0.02 0.040.05 0.04 0.06 0.02 0.06 0.05 −18.56 0.40 0.00 7.20 0.21 0.31 0.19 0.22SEQID-03127 0.02 0.06 0.03 0.04 0.06 0.03 0.04 0.07 −17.56 0.40 −0.016.33 0.56 0.71 0.00 0.20 SEQID-03128 0.02 0.06 0.04 0.04 0.09 0.02 0.050.08 −16.71 0.43 0.00 7.69 0.54 0.70 0.20 0.23 SEQID-03129 0.03 0.070.04 0.05 0.07 0.02 0.05 0.05 −17.23 0.44 −0.02 6.08 0.21 0.33 0.23 0.21SEQID-03130 0.03 0.09 0.04 0.06 0.05 0.03 0.05 0.03 −13.47 0.77 0.039.36 0.20 0.33 0.20 0.21 SEQID-03131 0.02 0.05 0.04 0.06 0.05 0.00 0.050.06 −21.15 0.40 −0.01 5.88 0.19 0.33 0.00 0.22 SEQID-03132 0.02 0.070.05 0.06 0.06 0.02 0.06 0.05 −20.38 0.37 −0.01 6.55 0.20 0.33 0.20 0.20SEQID-03133 0.02 0.07 0.04 0.07 0.05 0.03 0.05 0.06 −18.93 0.32 −0.016.24 0.18 0.35 0.19 0.20 SEQID-03134 0.02 0.05 0.02 0.04 0.10 0.03 0.090.07 −13.89 0.33 −0.01 5.92 0.24 0.31 0.00 0.26 SEQID-03135 0.04 0.070.03 0.08 0.09 0.04 0.02 0.08 −11.66 0.50 0.03 9.90 0.00 0.30 0.28 0.25SEQID-03136 0.02 0.05 0.03 0.07 0.05 0.01 0.03 0.07 −25.76 0.21 0.0910.74 0.22 0.31 0.20 0.00 SEQID-03137 0.01 0.04 0.02 0.09 0.06 0.06 0.040.09 −19.09 0.44 −0.02 5.99 0.22 0.31 0.00 0.20 SEQID-03138 0.01 0.060.04 0.05 0.05 0.04 0.06 0.05 −21.71 0.32 −0.02 6.32 0.21 0.33 0.00 0.00SEQID-03139 0.02 0.07 0.04 0.06 0.05 0.03 0.05 0.06 −16.14 0.42 −0.034.74 0.36 0.50 0.00 0.22 SEQID-03140 0.02 0.05 0.07 0.09 0.05 0.03 0.020.05 −17.71 0.32 0.00 6.92 0.21 0.34 0.21 0.23 SEQID-03141 0.02 0.050.04 0.05 0.06 0.01 0.03 0.03 −20.24 0.46 0.00 7.17 0.21 0.33 0.21 0.22SEQID-03142 0.01 0.07 0.04 0.07 0.05 0.01 0.06 0.06 −17.74 0.41 −0.016.16 0.20 0.33 0.00 0.22 SEQID-03143 0.01 0.06 0.04 0.10 0.08 0.05 0.060.06 −12.84 0.45 −0.01 5.65 0.21 0.34 0.00 0.21 SEQID-03144 0.02 0.030.05 0.04 0.05 0.03 0.07 0.07 −19.25 0.38 0.00 6.95 0.26 0.40 0.18 0.20SEQID-03145 0.02 0.05 0.03 0.04 0.05 0.03 0.05 0.07 −21.13 0.34 −0.016.35 0.21 0.33 0.00 0.21 SEQID-03146 0.03 0.06 0.04 0.04 0.05 0.02 0.030.06 −18.57 0.66 −0.02 5.13 0.19 0.34 0.00 0.30 SEQID-03147 0.01 0.010.03 0.04 0.04 0.00 0.07 0.08 −18.97 0.52 −0.01 5.70 0.31 0.36 0.24 0.25SEQID-03148 0.00 0.08 0.03 0.04 0.05 0.01 0.06 0.06 −24.21 0.19 0.1110.65 0.26 0.32 0.00 0.00 SEQID-03149 0.02 0.03 0.02 0.06 0.02 0.01 0.040.09 −19.28 0.56 0.10 11.02 0.23 0.30 0.24 0.22 SEQID-03150 0.02 0.050.01 0.04 0.10 0.05 0.10 0.07 −19.52 0.31 0.00 7.18 0.00 0.30 0.24 0.25SEQID-03151 0.02 0.04 0.07 0.04 0.03 0.04 0.05 0.07 −20.14 0.43 0.007.41 0.24 0.31 0.25 0.00 SEQID-03152 0.03 0.07 0.05 0.05 0.03 0.02 0.050.06 −23.90 0.27 0.13 11.56 0.21 0.29 0.00 0.23 SEQID-03153 0.01 0.050.03 0.02 0.06 0.01 0.05 0.06 −23.46 0.29 0.11 11.09 0.20 0.31 0.00 0.25SEQID-03154 0.02 0.03 0.03 0.05 0.05 0.01 0.03 0.0

−22.13 0.44 0.06 10.50 0.20 0.33 0.00 0.23 SEQID-03155 0.02 0.07 0.060.04 0.05 0.04 0.08 0.04 −20.56 0.29 0.00 7.23 0.24 0.33 0.22 0.00SEQID-03156 0.02 0.10 0.07 0.05 0.06 0.04 0.08 0.03 −18.82 0.29 0.008.30 0.24 0.31 0.00 0.21 SEQID-03157 0.03 0.07 0.07 0.06 0.10 0.03 0.050.06 −15.40 0.39 0.01 7.78 0.43 0.64 0.19 0.00 SEQID-03158 0.05 0.120.06 0.07 0.05 0.04 0.06 0.05 −19.34 0.32 −0.01 5.15 0.25 0.33 0.00 0.24SEQID-03159 0.04 0.05 0.03 0.04 0.06 0.01 0.06 0.05 −20.81 0.42 0.006.80 0.21 0.34 0.00 0.00 SEQID-03160 0.03 0.02 0.04 0.05 0.04 0.04 0.050.06 −17.94 0.47 −0.02 5.16 0.34 0.50 0.00 0.00 SEQID-03161 0.04 0.060.04 0.05 0.04 0.03 0.04 0.09 −20.27 0.40 0.01 7.31 0.21 0.31 0.22 0.20SEQID-03162 0.01 0.03 0.04 0.03 0.03 0.05 0.09 0.04 −21.74 0.27 −0.016.72 0.20 0.33 0.00 0.20 SEQID-03163 0.02 0.05 0.03 0.05 0.05 0.02 0.040.07 −21.91 0.44 0.00 6.81 0.21 0.33 0.00 0.00 SEQID-03164 0.03 0.050.04 0.03 0.03 0.01 0.06 0.07 −19.

2 0.48 −0.01 6.16 0.25 0.39 0.00 0.20 SEQID-03165 0.01 0.06 0.05 0.060.06 0.04 0.05 0.05 −20.50 0.34 0.00 6.93 0.21 0.31 0.00 0.21SEQID-03166 0.02 0.05 0.06 0.05 0.05 0.01 0.04 0.05 −19.02 0.38 −0.025.74 0.22 0.35 0.00 0.22 SEQID-03167 0.02 0.06 0.05 0.07 0.07 0.01 0.040.08 −15.61 0.47 −0.01 6.34 0.49 0.84 0.21 0.21 SEQID-03168 0.02 0.050.05 0.05 0.06 0.03 0.04 0.07 −18.10 0.42 −0.01 6.13 0.51 0.71 0.20 0.21SEQID-03169 0.03 0.05 0.05 0.05 0.06 0.00 0.09 0.08 −18.31 0.47 −0.015.40 0.22 0.34 0.22 0.23 SEQID-03170 0.02 0.09 0.06 0.05 0.04 0.03 0.050.06 −18.69 0.25 0.00 6.94 0.35 0.55 0.00 0.21 SEQID-03171 0.01 0.040.05 0.06 0.05 0.04 0.04 0.09 −19.15 0.39 −0.02 6.05 0.20 0.33 0.00 0.21SEQID-03172 0.02 0.04 0.04 0.05 0.06 0.02 0.05 0.09 −18.65 0.46 −0.016.13 0.21 0.35 0.00 0.21 SEQID-03173 0.02 0.05 0.04 0.06 0.05 0.02 0.050.07 −19.08 0.43 −0.01 5.87 0.00 0.36 0.00 0.19 SEQID-03174 0.01 0.010.04 0.06 0.07 0.01 0.04 0.08 −23.53 0.27 0.07 10.34 0.26 0.30 0.00 0.25SEQID-03175 0.03 0.05 0.04 0.04 0.03 0.02 0.01 0.09 −24.39 0.38 0.1311.46 0.22 0.30 0.21 0.24 SEQID-03176 0.02 0.04 0.03 0.04 0.03 0.00 0.090.07 −20.30 0.46 0.11 10.74 0.22 0.29 0.24 0.00 SEQID-03177 0.02 0.030.06 0.07 0.07 0.02 0.04 0.05 −21.07 0.32 0.12 11.31 0.00 0.30 0.18 0.21SEQID-03178 0.02 0.02 0.06 0.06 0.05 0.01 0.01 0.09 −21.32 0.43 0.039.87 0.26 0.33 0.23 0.24 SEQID-03179 0.01 0.07 0.02 0.04 0.07 0.01 0.060.07 −22.64 0.21 0.16 11.37 0.21 0.29 0.19 0.23 SEQID-03180 0.02 0.030.03 0.05 0.07 0.00 0.04 0.06 −25.68 0.26 0.14 11.09 0.24 0.30 0.00 0.00SEQID-03181 0.04 0.05 0.04 0.03 0.06 0.00 0.06 0.0

−21.97 0.25 0.11 10.99 0.22 0.28 0.00 0.19 SEQID-03182 0.01 0.05 0.040.05 0.06 0.00 0.02 0.04 −23.82 0.39 0.15 11.77 0.00 0.32 0.00 0.24SEQID-03183 0.03 0.04 0.04 0.06 0.03 0.01 0.03 0.07 −22.66 0.40 0.0910.61 0.23 0.32 0.20 0.20 SEQID-03184 0.01 0.08 0.03 0.04 0.07 0.04 0.020.05 −13.56 0.91 0.04 9.96 0.21 0.32 0.22 0.19 SEQID-03185 0.01 0.050.05 0.06 0.05 0.0

0.05 0.10 −20.75 0.33 −0.01 6.52 0.20 0.31 0.00 0.00 SEQID-03186 0.040.04 0.05 0.04 0.04 0.02 0.02 0.09 −17.89 0.52 −0.04 5.16 0.24 0.32 0.000.20 SEQID-03187 0.06 0.03 0.03 0.06 0.05 0.02 0.03 0.09 −19.76 0.430.00 7.02 0.19 0.29 0.00 0.00 SEQID-03188 0.04 0.05 0.04 0.06 0.05 0.030.09 0.05 −17.81 0.34 −0.01 6.51 0.18 0.31 0.00 0.21 SEQID-03189 0.020.03 0.06 0.05 0.04 0.05 0.04 0.07 −19.54 0.34 0.00 6.92 0.22 0.33 0.000.00 SEQID-03190 0.03 0.06 0.03 0.03 0.05 0.02 0.09 0.05 −21.71 0.44−0.05 4.46 0.21 0.33 0.18 0.17 SEQID-03191 0.03 0.03 0.04 0.07 0.04 0.000.039 0.10 −17.00 0.45 0.00 6.52 0.21 0.34 0.00 0.20 SEQID-03192 0.030.03 0.04 0.06 0.04 0.02 0.08 0.07 −19.23 0.37 −0.01 6.52 0.20 0.30 0.000.00 SEQID-03193 0.03 0.04 0.04 0.05 0.03 0.01 0.06 0.08 −19.80 0.43−0.01 6.29 0.21 0.33 0.00 0.21 SEQID-03194 0.02 0.10 0.05 0.08 0.03 0.050.05 0.06 −17.54 0.41 0.01 7.55 0.00 0.32 0.00 0.20 SEQID-03195 0.030.04 0.04 0.06 0.07 0.01 0.05 0.07 −17.53 0.44 0.01 8.79 0.19 0.33 0.000.00 SEQID-03196 0.01 0.05 0.07 0.06 0.05 0.01 0.03 0.08 −16.08 0.540.00 6.79 0.23 0.32 0.00 0.20 SEQID-03197 0.03 0.04 0.05 0.04 0.06 0.040.05 0.05 −21.77 0.37 −0.01 6.53 0.10 0.31 0.00 0.21 SEQID-03198 0.020.05 0.05 0.04 0.04 0.03 0.04 0.05 −19.67 0.43 −0.02 6.25 0.21 0.31 0.000.21 SEQID-03199 0.02 0.04 0.06 0.05 0.07 0.04 0.03 0.05 −18.77 0.41−0.03 4.85 0.21 0.33 0.00 0.22 SEQID-03200 0.03 0.03 0.02 0.08 0.06 0.020.04 0.08 −19.56 0.40 −0.01 6.64 0.21 0.36 0.13 0.22 SEQID-03201 0.030.06 0.03 0.04 0.04 0.03 0.04 0.05 −19.13 0.47 0.00 7.63 0.20 0.34 0.210.24 SEQID-03202 0.03 0.06 0.03 0.04 0.06 0.03 0.04 0.06 −19.73 0.370.01 7.59 0.21 0.34 0.00 0.21 SEQID-03203 0.02 0.05 0.06 0.04 0.05 0.020.04 0.06 −18.35 0.41 −0.01 6.24 0.21 0.33 0.00 0.23 SEQID-03204 0.040.06 0.03 0.03 0.05 0.01 0.04 0.07 −23.29 0.40 −0.02 5.84 0.21 0.32 0.190.21 SEQID-03205 0.04 0.05 0.04 0.05 0.06 0.01 0.05 0.07 −20.04 0.39−0.02 5.26 0.22 0.32 0.00 0.21 SEQID-03206 0.01 0.07 0.05 0.05 0.05 0.030.07 0.05 −19.44 0.36 −0.01 6.21 0.21 0.31 0.00 0.20 SEQID-03207 0.010.08 0.05 0.05 0.06 0.05 0.05 0.06 −19.96 0.34 −0.02 5.78 0.34 0.59 0.000.21 SEQID-03208 0.01 0.08 0.05 0.06 0.05 0.03 0.06 0.06 −20.97 0.33−0.02 6.23 0.21 0.32 0.00 0.21 SEQID-03209 0.03 0.06 0.06 0.05 0.05 0.040.05 0.06 −18.60 0.29 −0.04 5.00 0.38 0.78 0.00 0.21 SEQID-03210 0.040.06 0.06 0.05 0.04 0.01 0.05 0.07 −17.85 0.39 0.04 9.85 0.20 0.33 0.000.21 SEQID-03211 0.02 0.05 0.04 0.05 0.05 0.03 0.04 0.07 −20.85 0.38−0.01 5.93 0.23 0.36 0.00 0.21 SEQID-03212 0.02 0.04 0.04 0.05 0.05 0.010.05 0.09 −20.43 0.43 0.01 9.10 0.20 0.33 0.19 0.20 SEQID-03213 0.010.05 0.04 0.06 0.05 0.02 0.05 0.06 −19.53 0.38 −0.02 5.97 0.19 0.34 0.200.20 SEQID-03214 0.01 0.03 0.01 0.03 0.06 0.00 0.06 0.06 −23.82 0.320.18 11.91 0.25 0.32 0.00 0.27 SEQID-03215 0.01 0.03 0.03 0.06 0.05 0.020.0

0.06 −23.53 0.31 0.17 11.20 0.00 0.27 0.00 0.22 SEQID-03216 0.02 0.040.04 0.08 0.03 0.02 0.07 0.07 −20.29 0.26 0.18 12.08 0.26 0.29 0.25 0.19SEQID-03217 0.02 0.05 0.03 0.04 0.06 0.00 0.02 0.04 −23.81 0.32 0.1512.05 0.27 0.33 0.00 0.23 SEQID-03218 0.02 0.04 0.05 0.04 0.07 0.00 0.030.07 −25.82 0.26 0.08 11.01 0.21 0.30 0.00 0.24 SEQID-03219 0.02 0.050.05 0.03 0.04 0.02 0.05 0.07 −22.01 0.33 0.13 11.13 0.00 0.33 0.00 0.23SEQID-03220 0.09 0.06 0.20 0.01 0.03 0.01 0.00 0.05 −15.94 0.30 0.0510.92 0.29 0.39 0.26 0.32 SEQID-03221 0.03 0.04 0.04 0.05 0.07 0.00 0.020.10 −20.37 0.49 0.06 10.80 0.22 0.30 0.00 0.26 SEQID-03222 0.01 0.050.04 0.05 0.05 0.00 0.01 0.10 −24.53 0.39 0.07 10.84 0.21 0.32 0.00 0.22SEQID-03223 0.03 0.03 0.07 0.06 0.05 0.03 0.04 0.07 −20.93 0.28 −0.034.70 0.23 0.30 0.00 0.22 SEQID-03224 0.02 0.03 0.04 0.07 0.05 0.02 0.100.06 −21.73 0.39 0.00 6.96 0.21 0.32 0.00 0.19 SEQID-03225 0.03 0.010.02 0.03 0.04 0.02 0.02 0.06 −28.52 0.22 0.20 12.12 0.22 0.32 0.21 0.22SEQID-03226 0.01 0.03 0.03 0.05 0.05 0.02 0.05 0.04 −23.70 0.14 0.1311.45 0.23 0.30 0.22 0.19 SEQID-03227 0.02 0.04 0.03 0.05 0.06 0.01 0.050.10 −21.72 0.46 0.02 9.07 0.22 0.31 0.22 0.21 SEQID-03228 0.00 0.030.03 0.05 0.06 0.01 0.08 0.06 −21.24 0.35 −0.02 5.72 0.22 0.32 0.00 0.00SEQID-03229 0.03 0.04 0.04 0.04 0.06 0.01 0.04 0.11 −18.46 0.55 −0.016.36 0.20 0.34 0.22 0.00 SEQID-03230 0.02 0.06 0.03 0.05 0.06 0.01 0.030.10 −17.47 0.56 0.01 8.42 0.25 0.33 0.00 0.20 SEQID-03231 0.03 0.050.04 0.03 0.03 0.00 0.06 0.05 −19.05 0.35 0.00 6.73 0.00 0.32 0.00 0.00SEQID-03232 0.01 0.04 0.04 0.05 0.07 0.01 0.03 0.05 −20.32 0.40 0.006.81 0.21 0.31 0.00 0.00 SEQID-03233 0.04 0.07 0.03 0.04 0.06 0.01 0.050.06 −22.57 0.41 0.00 7.08 0.21 0.32 0.00 0.00 SEQID-03234 0.03 0.050.04 0.04 0.06 0.03 0.06 0.06 −20.07 0.38 −0.03 5.55 0.20 0.31 0.00 0.19SEQID-03235 0.01 0.04 0.03 0.04 0.05 0.01 0.04 0.09 −22.51 0.37 −0.016.59 0.19 0.31 0.00 0.00 SEQID-03236 0.02 0.06 0.07 0.08 0.10 0.01 0.070.06 −12.65 0.42 −0.04 4.25 0.20 0.35 0.00 0.22 SEQID-03237 0.03 0.040.02 0.09 0.06 0.04 0.03 0.05 −18.70 0.42 0.00 6.76 0.21 0.35 0.00 0.21SEQID-03238 0.02 0.06 0.03 0.06 0.06 0.02 0.05 0.06 −17.19 0.55 −0.034.58 0.20 0.31 0.25 0.00 SEQID-03239 0.03 0.07 0.02 0.03 0.05 0.02 0.030.04 −21.62 0.41 −0.06 4.29 0.21 0.35 0.00 0.00 SEQID-03240 0.06 0.050.06 0.05 0.04 0.01 0.04 0.09 −18.85 0.46 −0.01 6.38 0.00 0.33 0.00 0.21SEQID-03241 0.03 0.06 0.06 0.06 0.07 0.03 0.05 0.04 −20.80 0.30 0.006.80 0.20 0.31 0.00 0.18 SEQID-03242 0.02 0.04 0.05 0.07 0.05 0.02 0.050.08 −19.28 0.45 0.00 7.65 0.22 0.32 0.00 0.22 SEQID-03243 0.01 0.040.06 0.04 0.06 0.05 0.03 0.05 −18.94 0.41 0.00 7.11 0.22 0.32 0.00 0.22SEQID-03244 0.02 0.08 0.05 0.06 0.06 0.07 0.05 0.05 −15.37 0.40 −0.016.24 0.21 0.33 0.00 0.20 SEQID-03245 0.02 0.04 0.05 0.04 0.06 0.04 0.040.04 −18.05 0.44 −0.02 6.25 0.23 0.35 0.20 0.22 SEQID-03246 0.00 0.040.04 0.07 0.04 0.02 0.06 0.11 −17.67 0.48 0.00 7.36 0.23 0.34 0.00 0.21SEQID-03247 0.03 0.05 0.05 0.05 0.05 0.01 0.06 0.04 −19.69 0.31 0.007.20 0.20 0.38 0.00 0.22 SEQID-03248 0.02 0.05 0.05 0.04 0.03 0.03 0.040.07 −20.12 0.41 −0.01 6.60 0.20 0.56 0.00 0.23 SEQID-03249 0.05 0.060.04 0.06 0.04 0.03 0.04 0.07 −13.17 0.92 0.01 8.54 0.22 0.34 0.00 0.22SEQID-03250 0.03 0.04 0.06 0.05 0.07 0.03 0.04 0.06 −18.89 0.38 −0.016.37 0.21 0.31 0.00 0.21 SEQID-03251 0.02 0.06 0.05 0.06 0.04 0.01 0.040.07 −21.06 0.40 −0.01 6.27 0.21 0.34 0.18 0.22 SEQID-03252 0.03 0.030.02 0.05 0.04 0.03 0.05 0.06 −24.02 0.32 0.01 8.68 0.23 0.33 0.19 0.22SEQID-03253 0.03 0.06 0.05 0.06 0.03 0.02 0.04 0.06 −20.06 0.38 −0.016.73 0.21 0.33 0.00 0.21 SEQID-03254 0.04 0.05 0.04 0.06 0.05 0.02 0.030.06 −18.37 0.41 −0.01 6.41 0.21 0.32 0.00 0.22 SEQID-03255 0.03 0.080.04 0.04 0.06 0.04 0.06 0.07 −14.89 0.76 0.01 7.81 0.21 0.32 0.00 0.21SEQID-03256 0.03 0.05 0.04 0.04 0.06 0.02 0.05 0.05 −20.06 0.33 −0.016.69 0.20 0.34 0.00 0.21 SEQID-03257 0.03 0.05 0.06 0.05 0.04 0.01 0.050.05 −22.75 0.32 0.00 7.14 0.21 0.31 0.19 0.21 SEQID-03258 0.01 0.040.05 0.04 0.07 0.04 0.05 0.08 −18.56 0.43 0.00 7.05 0.20 0.33 0.00 0.21SEQID-03259 0.02 0.05 0.03 0.05 0.06 0.01 0.03 0.07 −22.67 0.39 −0.044.80 0.64 0.83 0.00 0.21 SEQID-03260 0.03 0.08 0.04 0.06 0.07 0.04 0.060.06 −15.35 0.63 0.00 7.32 0.20 0.32 0.00 0.21 SEQID-03261 0.04 0.050.05 0.04 0.04 0.00 0.03 0.06 −22.98 0.36 −0.04 4.68 0.18 0.34 0.00 0.21SEQID-03262 0.03 0.04 0.03 0.05 0.05 0.02 0.03 0.06 −18.67 0.40 0.007.04 0.19 0.33 0.00 0.21 SEQID-03263 0.01 0.05 0.05 0.08 0.05 0.02 0.040.07 −18.10 0.66 0.00 6.69 0.18 0.32 0.18 0.20 SEQID-03264 0.02 0.050.05 0.05 0.05 0.02 0.05 0.07 −18.67 0.47 0.00 7.29 0.20 0.33 0.19 0.20SEQID-03265 0.02 0.03 0.05 0.04 0.05 0.02 0.04 0.06 −23.47 0.32 −0.026.17 0.19 0.34 0.19 0.19 SEQID-03266 0.03 0.09 0.04 0.05 0.04 0.03 0.070.05 −17.08 0.61 0.02 9.11 0.18 0.33 0.19 0.13 SEQID-03267 0.01 0.030.02 0.04 0.06 0.05 0.05 0.07 −26.35 0.30 0.01 7.85 0.26 0.28 0.27 0.23SEQID-03268 0.02 0.02 0.04 0.05 0.01 0.01 0.05 0.10 −23.54 0.31 0.1611.12 0.27 0.33 0.24 0.29 SEQID-03269 0.01 0.01 0.03 0.07 0.00 0.00 0.030.07 −20.95 0.42 0.03 10.68 0.25 0.31 0.26 0.00 SEQID-03270 0.03 0.060.04 0.03 0.04 0.04 0.04 0.05 −23.36 0.23 0.04 9.56 0.23 0.33 0.25 0.27SEQID-03271 0.01 0.07 0.05 0.06 0.06 0.01 0.05 0.13 −11.59 0.55 0.007.24 0.27 0.31 0.23 0.27 SEQID-03272 0.02 0.03 0.04 0.12 0.07 0.00 0.040.04 −21.64 0.22 0.13 10.94 0.27 0.32 0.00 0.26 SEQID-03273 0.04 0.050.09 0.06 0.07 0.03 0.06 0.02 −17.54 0.44 0.00 7.34 0.22 0.28 0.23 0.29SEQID-03274 0.01 0.06 0.06 0.04 0.04 0.01 0.04 0.05 −19.71 0.44 0.006.88 0.00 0.30 0.25 0.21 SEQID-03275 0.01 0.05 0.04 0.06 0.02 0.02 0.010.09 −24.57 0.37 0.14 11.24 0.00 0.31 0.00 0.23 SEQID-03276 0.02 0.040.03 0.05 0.05 0.01 0.03 0.05 −25.87 0.20 0.22 12.19 0.00 0.29 0.23 0.22SEQID-03277 0.04 0.05 0.06 0.08 0.05 0.01 0.05 0.05 −17.99 0.52 −0.015.28 0.23 0.31 0.25 0.24 SEQID-03278 0.02 0.04 0.06 0.03 0.03 0.03 0.090.05 −23.44 0.24 0.05 10.04 0.23 0.33 0.23 0.24 SEQID-03279 0.04 0.120.05 0.06 0.05 0.06 0.07 0.05 −16.94 0.34 −0.03 4.74 0.21 0.29 0.22 0.24SEQID-03280 0.04 0.08 0.03 0.06 0.04 0.01 0.08 0.08 −23.77 0.34 −0.054.37 0.56 0.61 0.00 0.19 SEQID-03281 0.02 0.07 0.06 0.06 0.05 0.02 0.060.02 −18.20 0.32 0.03 9.82 0.24 0.31 0.23 0.00 SEQID-03282 0.02 0.070.01 0.06 0.06 0.00 0.07 0.05 −20.98 0.65 0.05 9.94 0.21 0.32 0.00 0.24SEQID-03283 0.02 0.04 0.04 0.08 0.05 0.02 0.01 0.08 −20.15 0.42 0.018.11 0.18 0.33 0.20 0.24 SEQID-03284 0.01 0.04 0.01 0.08 0.08 0.02 0.060.07 −19.83 0.40 0.00 6.79 0.00 0.31 0.22 0.00 SEQID-03285 0.02 0.040.08 0.06 0.05 0.04 0.03 0.06 −16.16 0.48 −0.01 6.51 0.19 0.31 0.00 0.23SEQID-03286 0.01 0.04 0.04 0.04 0.05 0.05 0.05 0.02 −17.98 0.31 0.017.90 0.51 0.66 0.00 0.00 SEQID-03287 0.04 0.04 0.03 0.04 0.06 0.03 0.060.09 −16.83 0.43 −0.02 5.59 0.20 0.32 0.23 0.00 SEQID-03288 0.03 0.070.06 0.04 0.02 0.04 0.06 0.06 −22.43 0.32 −0.02 6.37 0.00 0.33 0.00 0.00SEQID-03289 0.01 0.04 0.05 0.05 0.06 0.02 0.02 0.10 −17.38 0.54 −0.015.87 0.57 0.68 0.00 0.18 SEQID-03290 0.02 0.09 0.08 0.05 0.05 0.04 0.050.04 −15.00 0.25 −0.02 4.98 0.27 0.41 0.22 0.25 SEQID-03291 0.04 0.050.02 0.05 0.06 0.01 0.02 0.07 −22.01 0.41 −0.05 4.84 0.23 0.30 0.00 0.21SEQID-03292 0.05 0.06 0.03 0.05 0.09 0.01 0.02 0.07 −18.19 0.51 −0.016.36 0.20 0.31 0.21 0.00 SEQID-03293 0.03 0.08 0.05 0.06 0.03 0.04 0.050.08 −17.68 0.69 0.04 10.16 0.22 0.31 0.20 0.22 SEQID-03294 0.02 0.100.06 0.04 0.09 0.05 0.09 0.05 −11.08 0.66 0.07 10.46 0.22 0.30 0.00 0.00SEQID-03295 0.03 0.05 0.03 0.06 0.07 0.02 0.09 0.05 −18.78 0.34 −0.016.16 0.19 0.32 0.00 0.00 SEQID-03296 0.02 0.04 0.03 0.06 0.05 0.01 0.030.08 −19.15 0.47 0.01 8.42 0.21 0.33 0.00 0.00 SEQID-03297 0.00 0.110.03 0.04 0.04 0.07 0.08 0.07 −11.44 1.03 0.02 9.04 0.20 0.30 0.00 0.22SEQID-03298 0.02 0.05 0.03 0.05 0.04 0.01 0.09 0.07 −19.38 0.42 0.0310.12 0.21 0.32 0.21 0.00 SEQID-03299 0.03 0.05 0.04 0.06 0.07 0.00 0.080.06 −16.95 0.52 −0.01 5.76 0.00 0.32 0.00 0.00 SEQID-03300 0.01 0.070.04 0.03 0.09 0.01 0.04 0.09 −17.72 0.54 0.02 9.70 0.23 0.35 0.00 0.21SEQID-03301 0.03 0.04 0.04 0.04 0.07 0.02 0.04 0.06 −19.05 0.48 −0.015.81 0.00 0.36 0.00 0.20 SEQID-03302 0.02 0.02 0.04 0.05 0.06 0.02 0.060.08 −17.63 0.45 0.00 6.86 0.45 0.56 0.00 0.20 SEQID-03303 0.03 0.040.05 0.05 0.04 0.01 0.03 0.07 −16.74 0.83 0.00 7.03 0.23 0.33 0.21 0.23SEQID-03304 0.01 0.05 0.06 0.04 0.04 0.02 0.03 0.08 −17.49 0.49 0.007.20 0.24 0.37 0.00 0.22 SEQID-03305 0.02 0.06 0.04 0.05 0.05 0.02 0.040.08 −20.38 0.46 −0.01 6.68 0.21 0.33 0.00 0.22 SEQID-03306 0.03 0.040.04 0.07 0.05 0.00 0.03 0.10 −17.13 0.50 0.01 7.88 0.21 0.33 0.00 0.17SEQID-03307 0.02 0.07 0.05 0.05 0.09 0.04 0.05 0.04 −14.77 0.44 −0.015.62 0.23 0.35 0.00 0.22 SEQID-03308 0.02 0.05 0.04 0.08 0.05 0.02 0.040.06 −18.98 0.43 0.01 7.64 0.21 0.35 0.00 0.22 SEQID-03309 0.02 0.040.04 0.03 0.06 0.01 0.03 0.05 −26.26 0.31 0.00 6.97 0.22 0.32 0.00 0.23SEQID-03310 0.02 0.06 0.05 0.07 0.07 0.02 0.05 0.07 −15.17 0.43 0.017.62 0.24 0.31 0.20 0.22 SEQID-03311 0.02 0.07 0.08 0.08 0.05 0.03 0.060.05 −16.81 0.49 0.01 7.97 0.21 0.32 0.00 0.20 SEQID-03312 0.04 0.030.04 0.05 0.03 0.00 0.03 0.08 −21.81 0.41 0.02 9.64 0.24 0.34 0.00 0.22SEQID-03313 0.03 0.05 0.02 0.04 0.07 0.01 0.04 0.08 −20.78 0.47 −0.025.19 0.21 0.32 0.00 0.20 SEQID-03314 0.02 0.04 0.04 0.05 0.06 0.03 0.070.06 −19.61 0.37 0.02 9.42 0.21 0.36 0.20 0.22 SEQID-03315 0.02 0.060.04 0.04 0.04 0.01 0.02 0.09 −20.60 0.46 0.01 8.22 0.22 0.32 0.00 0.22SEQID-03316 0.03 0.07 0.06 0.06 0.04 0.04 0.07 0.05 −18.95 0.34 0.007.31 0.21 0.34 0.00 0.23 SEQID-03317 0.02 0.05 0.05 0.06 0.05 0.02 0.050.05 −17.55 0.38 0.02 9.43 0.21 0.33 0.00 0.21 SEQID-03318 0.02 0.040.06 0.08 0.07 0.01 0.03 0.05 −19.66 0.40 0.00 8.17 0.21 0.35 0.19 0.24SEQID-03319 0.02 0.07 0.05 0.06 0.05 0.02 0.07 0.06 −19.89 0.37 −0.016.07 0.21 0.35 0.00 0.22 SEQID-03320 0.03 0.03 0.05 0.04 0.05 0.03 0.050.06 −18.30 0.45 0.00 6.89 0.21 0.33 0.00 0.22 SEQID-03321 0.04 0.060.03 0.05 0.04 0.02 0.03 0.06 −22.56 0.37 −0.01 6.34 0.21 0.33 0.20 0.23SEQID-03322 0.02 0.06 0.04 0.05 0.06 0.03 0.03 0.08 −19.07 0.49 0.006.74 0.20 0.34 0.21 0.21 SEQID-03323 0.01 0.05 0.04 0.05 0.05 0.02 0.060.08 −17.29 0.57 −0.02 5.65 0.22 0.40 0.00 0.21 SEQID-03324 0.03 0.060.05 0.07 0.05 0.01 0.09 0.06 −18.12 0.43 0.00 6.80 0.21 0.32 0.20 0.23SEQID-03325 0.01 0.03 0.05 0.08 0.08 0.02 0.05 0.06 −18.57 0.39 −0.016.46 0.20 0.34 0.00 0.23 SEQID-03326 0.02 0.07 0.04 0.07 0.05 0.02 0.040.08 −17.44 0.49 0.01 8.19 0.31 0.48 0.19 0.21 SEQID-03327 0.03 0.060.04 0.05 0.04 0.05 0.05 0.04 −22.15 0.32 −0.02 5.53 0.21 0.36 0.00 0.21SEQID-03328 0.03 0.05 0.05 0.06 0.06 0.02 0.02 0.06 −16.03 0.48 0.018.92 0.28 0.43 0.00 0.22 SEQID-03329 0.02 0.06 0.05 0.12 0.06 0.01 0.070.05 −13.60 0.41 −0.05 3.95 0.20 0.36 0.20 0.21 SEQID-03330 0.02 0.060.06 0.05 0.08 0.05 0.06 0.05 −17.92 0.32 −0.03 5.13 0.22 0.34 0.00 0.21SEQID-03331 0.02 0.07 0.06 0.05 0.05 0.05 0.04 0.05 −19.69 0.36 −0.044.95 0.20 0.35 0.00 0.21 SEQID-03332 0.02 0.08 0.06 0.07 0.06 0.03 0.030.05 −16.58 0.47 0.01 7.78 0.20 0.35 0.21 0.21 SEQID-03333 0.03 0.110.05 0.04 0.05 0.05 0.05 0.05 −15.34 0.71 0.01 8.35 0.20 0.32 0.00 0.21SEQID-03334 0.03 0.04 0.03 0.05 0.06 0.00 0.02 0.07 −21.94 0.41 −0.015.83 0.45 0.73 0.00 0.22 SEQID-03335 0.02 0.06 0.05 0.07 0.04 0.04 0.050.08 −15.52 0.75 0.02 9.45 0.19 0.35 0.00 0.20 SEQID-03336 0.02 0.060.05 0.05 0.07 0.02 0.04 0.08 −16.52 0.52 0.00 7.91 0.19 0.42 0.19 0.21SEQID-03337 0.02 0.05 0.06 0.08 0.06 0.03 0.04 0.07 −16.79 0.41 −0.034.92 0.23 0.41 0.00 0.22 SEQID-03338 0.03 0.08 0.04 0.04 0.06 0.03 0.040.05 −18.38 0.57 −0.03 5.16 0.18 0.34 0.00 0.20 SEQID-03339 0.02 0.050.04 0.05 0.06 0.01 0.05 0.07 −18.47 0.44 0.00 6.70 0.20 0.33 0.00 0.20SEQID-03340 0.03 0.08 0.04 0.06 0.06 0.03 0.06 0.06 −17.65 0.54 0.018.36 0.18 0.35 0.00 0.21 SEQID-03341 0.03 0.05 0.06 0.05 0.05 0.01 0.060.06 −19.20 0.38 0.04 9.98 0.19 0.36 0.00 0.21 SEQID-03342 0.02 0.050.06 0.04 0.06 0.03 0.05 0.05 −20.08 0.29 0.00 7.25 0.20 0.32 0.20 0.20SEQID-03343 0.03 0.06 0.05 0.04 0.05 0.04 0.03 0.05 −21.66 0.35 0.006.85 0.19 0.35 0.19 0.18 SEQID-03344 0.03 0.05 0.06 0.04 0.05 0.02 0.040.06 −23.33 0.36 −0.05 4.64 0.19 0.73 0.19 0.20 SEQID-03345 0.02 0.040.04 0.06 0.07 0.02 0.04 0.08 −17.42 0.52 −0.01 6.42 0.18 0.33 0.19 0.20SEQID-03346 0.04 0.05 0.05 0.05 0.08 0.01 0.04 0.07 −11.85 0.77 0.039.95 0.51 0.70 0.00 0.00 SEQID-03347 0.04 0.05 0.05 0.06 0.07 0.01 0.040.07 −11.94 0.76 0.04 10.04 0.52 0.70 0.00 0.21 SEQID-03348 0.03 0.090.05 0.05 0.06 0.02 0.05 0.08 −15.96 0.61 −0.01 6.14 0.21 0.33 0.00 0.23SEQID-03349 0.03 0.09 0.07 0.07 0.05 0.01 0.05 0.06 −18.41 0.41 0.007.53 0.21 0.34 0.20 0.21 SEQID-03350 0.05 0.05 0.05 0.06 0.05 0.02 0.060.06 −19.76 0.45 −0.02 5.86 0.20 0.33 0.00 0.20 SEQID-03351 0.02 0.040.04 0.02 0.05 0.07 0.10 0.05 −17.47 0.27 0.02 8.46 0.57 0.59 0.00 0.24SEQID-03352 0.02 0.05 0.04 0.06 0.06 0.01 0.02 0.10 −20.36 0.52 0.028.82 0.85 0.94 0.00 0.25 SEQID-03353 0.04 0.08 0.05 0.07 0.03 0.03 0.000.07 −26.77 0.30 −0.02 5.42 0.69 0.81 0.19 0.21 SEQID-03354 0.03 0.050.01 0.05 0.04 0.03 0.03 0.04 −17.00 0.34 0.01 7.63 0.35 0.39 0.25 0.29SEQID-03355 0.02 0.04 0.01 0.04 0.03 0.03 0.03 0.05 −18.73 0.33 0.017.63 0.38 0.43 0.25 0.34 SEQID-03356 0.02 0.06 0.04 0.03 0.06 0.03 0.060.06 −19.94 0.35 −0.01 6.51 0.20 0.33 0.00 0.22 SEQID-03357 0.03 0.020.04 0.05 0.05 0.05 0.00 0.13 −20.80 0.43 0.05 9.60 0.30 0.26 0.00 1.00SEQID-03358 0.02 0.01 0.02 0.02 0.06 0.02 0.04 0.08 −24.50 0.28 0.1912.27 0.20 0.29 0.00 0.26 SEQID-03359 0.02 0.06 0.03 0.04 0.05 0.01 0.040.07 −20.90 0.43 −0.02 5.34 0.21 0.33 0.00 0.22 SEQID-03360 0.02 0.040.05 0.05 0.04 0.00 0.03 0.04 −27.42 0.25 0.13 10.79 0.26 0.33 0.25 0.25SEQID-03361 0.02 0.04 0.04 0.07 0.10 0.01 0.06 0.08 −9.68 0.87 0.02 9.720.66 0.34 0.26 0.25 SEQID-03362 0.03 0.06 0.05 0.03 0.02 0.01 0.03 0.06−21.73 0.28 0.14 11.17 0.21 0.29 0.19 0.23 SEQID-03363 0.02 0.05 0.040.06 0.06 0.02 0.05 0.06 −22.51 0.37 −0.03 5.01 0.19 0.32 0.00 0.20SEQID-03364 0.03 0.05 0.04 0.04 0.05 0.01 0.03 0.06 −22.74 0.37 0.1110.93 0.19 0.32 0.00 0.20 SEQID-03365 0.04 0.04 0.03 0.05 0.10 0.01 0.050.08 −10.26 0.95 0.04 10.29 0.74 0.36 0.00 0.25 SEQID-03366 0.03 0.090.05 0.06 0.06 0.05 0.04 0.06 −12.29 0.53 0.04 9.54 0.31 0.42 0.00 0.22SEQID-03367 0.03 0.04 0.05 0.09 0.05 0.02 0.05 0.06 −14.63 0.57 0.007.65 0.24 0.32 0.00 0.24 SEQID-03368 0.02 0.05 0.05 0.05 0.05 0.00 0.030.10 −16.64 0.55 0.00 6.28 0.54 0.73 0.00 0.00 SEQID-03369 0.04 0.050.08 0.03 0.05 0.04 0.04 0.04 −17.25 0.45 −0.03 4.77 0.21 0.36 0.00 0.00SEQID-03370 0.06 0.05 0.04 0.00 0.04 0.00 0.02 0.05 −26.32 0.37 0.048.90 0.25 0.25 0.25 0.00 SEQID-03371 0.02 0.03 0.03 0.08 0.01 0.00 0.030.07 −20.23 0.45 0.10 10.98 0.26 0.32 0.25 0.24 SEQID-03372 0.02 0.040.04 0.07 0.09 0.01 0.05 0.09 −9.77 0.87 0.03 9.83 0.68 0.85 0.20 0.25SEQID-03373 0.04 0.03 0.02 0.06 0.03 0.02 0.02 0.08 −17.25 0.59 −0.024.93 0.26 0.31 0.24 0.00 SEQID-03374 0.03 0.07 0.03 0.06 0.06 0.02 0.040.07 −19.34 0.47 0.04 9.86 0.57 0.84 0.24 0.24 SEQID-03375 0.02 0.030.02 0.03 0.08 0.00 0.02 0.04 −23.63 0.33 0.00 7.82 0.22 0.31 0.00 0.00SEQID-03376 0.04 0.04 0.02 0.08 0.04 0.01 0.02 0.10 −16.89 0.58 0.039.87 0.27 0.37 0.19 0.00 SEQID-03377 0.03 0.02 0.04 0.06 0.05 0.03 0.030.10 −17.05 0.55 0.00 6.78 0.26 0.33 0.20 0.22 SEQID-03378 0.02 0.050.04 0.05 0.06 0.00 0.04 0.07 −19.37 0.46 −0.03 4.82 0.23 0.33 0.00 0.21SEQID-03379 0.04 0.05 0.03 0.04 0.04 0.00 0.04 0.07 −23.44 0.42 −0.035.37 0.21 0.31 0.19 0.00 SEQID-03380 0.03 0.05 0.04 0.05 0.06 0.02 0.020.07 −16.45 0.54 −0.01 6.09 0.29 0.38 0.20 0.23 SEQID-03381 0.04 0.060.04 0.05 0.04 0.01 0.05 0.07 −21.01 0.38 −0.01 6.34 0.19 0.31 0.00 0.20SEQID-03382 0.02 0.05 0.04 0.03 0.07 0.00 0.02 0.05 −23.97 0.30 0.1511.86 0.23 0.31 0.26 0.00 SEQID-03383 0.03 0.07 0.04 0.04 0.05 0.01 0.040.09 −17.64 0.57 0.02 8.47 0.91 0.98 0.22 0.94 SEQID-03384 0.02 0.070.05 0.05 0.05 0.01 0.05 0.09 −17.85 0.54 0.00 7.45 0.94 0.96 0.00 0.94SEQID-03385 0.02 0.04 0.02 0.03 0.08 0.00 0.02 0.05 −23.64 0.33 0.007.90 0.22 0.31 0.23 0.21 SEQID-03386 0.04 0.10 0.04 0.03 0.06 0.00 0.050.09 −19.69 0.44 0.05 9.49 0.85 0.83 0.00 0.85 SEQID-03387 0.01 0.070.06 0.07 0.05 0.01 0.05 0.07 −14.46 0.61 0.01 7.89 0.78 0.98 0.23 0.92SEQID-03388 0.03 0.06 0.04 0.05 0.08 0.01 0.06 0.05 −17.52 0.43 −0.034.85 0.87 0.98 0.00 0.20 SEQID-03389 0.05 0.04 0.05 0.05 0.06 0.02 0.050.06 −19.76 0.44 −0.03 5.29 0.21 0.31 0.00 0.21 SEQID-03390 0.01 0.060.06 0.05 0.06 0.03 0.05 0.05 −20.16 0.37 −0.02 5.65 0.19 0.35 0.00 0.20SEQID-03391 0.03 0.04 0.05 0.08 0.06 0.00 0.02 0.04 −26.28 0.23 0.1310.87 0.28 0.32 0.25 0.26 SEQID-03392 0.02 0.03 0.01 0.02 0.06 0.00 0.060.07 −23.82 0.31 0.18 12.01 0.00 0.28 0.00 0.29 SEQID-03393 0.03 0.040.06 0.05 0.04 0.00 0.10 0.05 −16.95 0.53 0.00 7.08 0.25 0.32 0.26 0.98SEQID-03394 0.04 0.05 0.04 0.06 0.09 0.01 0.07 0.05 −17.36 0.37 −0.034.65 0.95 1.00 0.00 0.00 SEQID-03395 0.01 0.02 0.02 0.04 0.05 0.02 0.060.06 −26.96 0.40 −0.03 5.23 0.24 0.34 0.00 0.00 SEQID-03396 0.03 0.060.03 0.05 0.05 0.03 0.04 0.09 −20.88 0.47 0.00 6.80 0.86 0.93 0.23 0.21SEQID-03397 0.02 0.05 0.04 0.03 0.06 0.03 0.03 0.08 −24.40 0.39 −0.025.55 0.21 0.34 0.00 0.20 SEQID-03398 0.03 0.04 0.04 0.04 0.06 0.01 0.030.06 −22.95 0.36 −0.02 4.88 0.72 0.91 0.19 0.20 SEQID-03399 0.04 0.020.03 0.07 0.03 0.00 0.05 0.05 −29.35 0.21 0.02 9.01 0.98 0.69 0.00 0.34SEQID-03400 0.03 0.06 0.01 0.03 0.06 0.04 0.04 0.06 −20.96 0.45 0.006.96 0.22 0.31 0.00 0.25 SEQID-03401 0.03 0.05 0.05 0.04 0.06 0.01 0.040.08 −22.02 0.41 0.03 9.66 0.21 0.35 0.21 0.22 SEQID-03402 0.09 0.130.03 0.06 0.06 0.00 0.00 0.02 −18.17 0.56 0.07 8.61 0.29 0.29 0.30 0.28SEQID-03403 0.04 0.04 0.04 0.05 0.09 0.00 0.01 0.05 −23.24 0.34 0.0811.26 0.23 0.30 0.22 0.23 SEQID-03404 0.01 0.05 0.03 0.05 0.04 0.04 0.090.04 −18.45 0.29 −0.02 5.06 0.24 0.33 0.00 0.24 SEQID-03405 0.01 0.030.04 0.08 0.01 0.00 0.03 0.07 −18.26 0.35 0.09 11.09 0.25 0.31 0.27 0.22SEQID-03406 0.02 0.03 0.05 0.06 0.06 0.00 0.10 0.04 −15.35 0.46 0.006.76 0.24 0.32 0.25 0.81 SEQID-03407 0.03 0.06 0.04 0.04 0.04 0.02 0.060.08 −19.27 0.53 −0.02 5.37 0.21 0.33 0.20 0.22 SEQID-03408 0.02 0.080.06 0.04 0.05 0.02 0.06 0.06 −21.28 0.28 0.00 7.03 0.39 0.56 0.00 0.21SEQID-03409 0.02 0.05 0.04 0.06 0.06 0.03 0.05 0.07 −19.93 0.41 0.006.59 0.88 1.00 0.00 0.20 SEQID-03410 0.06 0.03 0.05 0.04 0.03 0.02 0.020.09 −19.41 0.55 0.12 11.19 0.25 0.30 0.25 0.24 SEQID-03411 0.02 0.070.05 0.05 0.05 0.01 0.05 0.09 −18.21 0.52 −0.04 4.58 0.82 0.91 0.21 0.82SEQID-03412 0.03 0.03 0.05 0.03 0.05 0.02 0.05 0.06 −19.98 0.38 0.007.14 0.22 0.32 0.23 0.22 SEQID-03413 0.02 0.04 0.03 0.05 0.04 0.02 0.050.08 −20.30 0.40 −0.01 5.55 0.89 0.96 0.21 0.22 SEQID-03414 0.03 0.050.04 0.04 0.05 0.01 0.07 0.06 −18.95 0.51 −0.01 5.86 0.20 0.33 0.00 0.20SEQID-03415 0.04 0.09 0.03 0.08 0.05 0.01 0.05 0.07 −13.29 0.89 −0.024.72 0.20 0.34 0.21 0.20 SEQID-03416 0.04 0.04 0.04 0.03 0.07 0.02 0.020.02 −21.96 0.35 0.12 11.31 0.24 0.31 0.00 0.28 SEQID-03417 0.04 0.080.04 0.03 0.08 0.02 0.00 0.08 −26.04 0.20 0.12 10.98 0.28 0.29 0.00 0.18SEQID-03418 0.06 0.02 0.03 0.02 0.02 0.00 0.08 0.09 −23.37 0.42 0.049.88 0.30 0.27 0.26 0.19 SEQID-03419 0.02 0.02 0.00 0.08 0.05 0.00 0.030.08 −24.14 0.27 −0.03 4.99 0.31 0.24 0.33 0.31 SEQID-03420 0.02 0.040.03 0.07 0.02 0.01 0.04 0.06 −23.80 0.29 0.00 7.24 0.23 0.33 0.22 0.21SEQID-03421 0.03 0.04 0.01 0.05 0.05 0.01 0.05 0.04 −22.10 0.45 0.2212.43 0.23 0.29 0.00 0.25 SEQID-03422 0.04 0.04 0.04 0.03 0.08 0.02 0.020.03 −20.50 0.33 0.15 11.74 0.26 0.29 0.00 0.25 SEQID-03423 0.01 0.040.05 0.05 0.04 0.04 0.03 0.05 −20.61 0.42 −0.02 5.73 0.21 0.33 0.20 0.22SEQID-03424 0.01 0.01 0.04 0.08 0.04 0.03 0.04 0.01 −23.48 0.39 0.1712.30 0.27 0.30 0.30 0.25 SEQID-03425 0.02 0.05 0.01 0.04 0.03 0.02 0.040.04 −37.76 0.22 −0.30 3.51 0.21 0.30 0.13 0.23 SEQID-03426 0.01 0.040.03 0.05 0.07 0.03 0.04 0.06 −23.41 0.28 −0.02 6.39 0.00 0.33 0.00 0.23SEQID-03427 0.02 0.02 0.04 0.06 0.05 0.03 0.04 0.04 −21.76 0.33 −0.015.87 0.21 0.33 0.22 0.25 SEQID-03428 0.02 0.02 0.05 0.08 0.05 0.00 0.030.03 −20.38 0.35 0.01 8.68 0.22 0.33 0.00 0.23 SEQID-03429 0.06 0.050.06 0.06 0.02 0.01 0.02 0.06 −21.84 0.28 0.08 10.52 0.25 0.33 0.00 0.27SEQID-03430 0.02 0.00 0.03 0.10 0.08 0.00 0.00 0.01 −24.63 0.17 0.006.95 0.29 0.25 0.32 0.32 SEQID-03431 0.02 0.04 0.02 0.05 0.04 0.03 0.010.02 −34.55 0.18 0.11 10.64 0.22 0.32 0.00 0.22 SEQID-03432 0.04 0.050.03 0.05 0.07 0.02 0.02 0.02 −23.50 0.27 0.15 11.53 0.25 0.28 0.00 0.00SEQID-03433 0.01 0.01 0.07 0.04 0.03 0.00 0.00 0.03 −21.17 0.34 −0.035.07 0.27 0.35 0.27 0.26 SEQID-03434 0.01 0.04 0.00 0.06 0.05 0.01 0.060.02 −24.25 0.30 0.24 12.58 0.25 0.28 0.00 0.23 SEQID-03435 0.03 0.000.02 0.04 0.00 0.00 0.00 0.04 −28.57 0.45 0.33 12.42 0.34 0.16 0.32 0.30SEQID-03436 0.07 0.05 0.05 0.05 0.05 0.01 0.02 0.07 −20.41 0.43 −0.016.26 0.22 0.30 0.26 0.23 SEQID-03437 0.07 0.13 0.03 0.05 0.05 0.02 0.070.01 −21.35 0.15 −0.12 3.96 0.22 0.20 0.21 0.27 SEQID-03438 0.02 0.070.03 0.06 0.04 0.02 0.05 0.05 −27.53 0.31 −0.26 3.23 0.24 0.28 0.00 0.24SEQID-03439 0.00 0.03 0.03 0.05 0.06 0.09 0.03 0.07 −20.71 0.39 −0.064.55 0.18 0.32 0.00 0.23 SEQID-03440 0.00 0.03 0.03 0.06 0.05 0.09 0.0

3 0.08 −21.25 0.38 −0.05 4.65 0.21 0.32 0.22 0.22 SEQID-03441 0.02 0.000.03 0.00 0.11 0.00 0.00 0.13 −20.61 0.26 0.09 11.27 0.30 0.23 0.00 0.29SEQID-03442 0.04 0.08 0.04 0.02 0.08 0.02 0.00 0.08 −26.48 0.23 0.1211.03 0.26 0.27 0.00 0.00 SEQID-03443 0.04 0.08 0.04 0.04 0.08 0.02 0.000.08 −25.24 0.20 0.13 11.21 0.26 0.27 0.00 0.00 SEQID-03444 0.01 0.020.16 0.09 0.04 0.01 0.06 0.05 −15.46 0.16 0.03 8.07 0.22 0.36 0.20 0.24SEQID-03445 0.02 0.02 0.02 0.09 0.04 0.01 0.04 0.03 −28.10 0.11 −0.054.66 0.23 0.38 0.00 0.21 SEQID-03446 0.03 0.06 0.04 0.05 0.05 0.01 0.020.06 −22.29 0.42 −0.03 5.11 0.22 0.33 0.00 0.23 SEQID-03447 0.00 0.020.10 0.27 0.03 0.00 0.04 0.06 −8.13 0.28 0.02 8.77 0.25 0.52 0.22 0.27SEQID-03448 0.02 0.01 0.02 0.07 0.05 0.01 0.03 0.05 −23.80 0.25 −0.025.21 0.25 0.36 0.20 0.22 SEQID-03449 0.04 0.04 0.01 0.09 0.03 0.01 0.050.05 −18.68 0.26 0.01 8.78 0.689 0.89 0.21 0.21 SEQID-03450 0.02 0.080.01 0.10 0.04 0.00 0.03 0.05 −16.79 0.24 −0.01 5.68 0.62 0.91 0.21 0.22SEQID-03451 0.02 0.03 0.11 0.03 0.05 0.05 0.03 0.05 −19.27 0.23 −0.016.42 0.22 0.32 0.23 0.25 SEQID-03452 0.05 0.02 0.03 0.0

0.04 0.01 0.04 0.05 −27.05 0.26 0.15 10.77 0.23 0.30 0.23 0.25SEQID-03453 0.02 0.03 0.02 0.05 0.04 0.01 0.05 0.02 −24.50 0.11 0.097.86 0.24 0.31 0.26 0.26 SEQID-03454 0.02 0.02 0.04 0.06 0.05 0.03 0.040.04 −22.24 0.31 −0.02 5.35 0.23 0.34 0.22 0.25 SEQID-03455 0.02 0.030.02 0.00 0.03 0.01 0.04 0.05 −39.36 0.23 −0.30 3.72 0.27 0.35 0.22 0.29SEQID-03456 0.01 0.00 0.11 0.02 0.01 0.00 0.00 0.02 −33.42 0.00 0.1110.67 0.32 0.31 0.30 0.31 SEQID-03457 0.01 0.00 0.11 0.03 0.02 0.00 0.000.02 −33.41 0.00 0.13 10.79 0.30 0.31 0.30 0.30 SEQID-03458 0.01 0.060.06 0.09 0.04 0.01 0.04 0.02 −20.91 0.13 0.13 11.83 0.26 0.31 0.00 0.27SEQID-03459 0.02 0.00 0.03 0.04 0.02 0.00 0.05 0.03 −36.62 0.10 0.5012.47 0.29 0.18 0.34 0.31 SEQID-03460 0.04 0.04 0.03 0.05 0.07 0.01 0.040.05 −20.18 0.49 0.00 6.51 0.22 0.32 0.23 0.24 SEQID-03461 0.01 0.050.05 0.03 0.06 0.01 0.04 0.09 −24.13 0.37 0.10 10.78 0.23 0.33 0.00 0.26SEQID-03462 0.05 0.04 0.02 0.03 0.04 0.04 0.06 0.03 −30.24 0.13 −0.016.54 0.27 0.31 0.00 0.00 SEQID-03463 0.04 0.00 0.02 0.05 0.04 0.01 0.050.02 −24.71 0.14 0.10 11.18 0.00 0.31 0.25 0.00 SEQID-03464 0.07 0.050.02 0.04 0.02 0.03 0.03 0.02 −20.78 0.43 0.15 12.24 0.25 0.28 0.21 0.22SEQID-03465 0.03 0.00 0.01 0.07 0.05 0.02 0.08 0.02 −25.38 0.12 0.0810.34 0.24 0.27 0.00 0.00 SEQID-03466 0.02 0.00 0.03 0.07 0.02 0.02 0.050.05 −24.70 0.38 0.15 11.02 0.22 0.26 0.00 0.00 SEQID-03467 0.04 0.060.04 0.13 0.04 0.03 0.05 0.04 −24.12 0.22 0.27 12.15 0.28 0.21 0.28 0.26SEQID-03468 0.04 0.04 0.00 0.03 0.02 0.03 0.00 0.03 −21.62 0.41 0.2012.60 0.30 0.20 0.28 0.30 SEQID-03469 0.10 0.03 0.03 0.03 0.03 0.04 0.000.03 −26.22 0.36 0.01 9.11 0.26 0.26 0.00 0.00 SEQID-03470 0.02 0.020.04 0.06 0.05 0.03 0.04 0.04 −22.20 0.32 −0.02 5.35 0.23 0.33 0.22 0.25SEQID-03471 0.01 0.00 0.09 0.04 0.04 0.00 0.00 0.00 −38.40 0.01 0.0710.28 0.32 0.32 0.27 0.29 SEQID-03472 0.02 0.03 0.08 0.05 0.01 0.02 0.010.04 −20.01 0.23 0.02 8.25 0.31 0.30 0.34 0.30 SEQID-03473 0.02 0.000.00 0.09 0.03 0.00 0.10 0.01 −45.36 0.00 0.63 13.20 0.30 0.21 0.34 0.27SEQID-03474 0.02 0.07 0.06 0.11 0.03 0.01 0.03 0.03 −20.32 0.14 0.1412.12 0.25 0.31 0.00 0.28 SEQID-03475 0.04 0.04 0.02 0.05 0.07 0.01 0.040.04 −20.61 0.48 0.00 7.29 0.23 0.31 0.24 0.24 SEQID-03476 0.02 0.040.01 0.05 0.05 0.01 0.07 0.04 −21.37 0.41 0.21 12.16 0.21 0.29 0.18 0.00SEQID-03477 0.03 0.06 0.04 0.03 0.00 0.04 0.00 0.02 −20.63 0.09 0.169.35 0.35 0.20 0.34 0.32 SEQID-03478 0.00 0.06 0.04 0.03 0.00 0.04 0.000.06 −20.63 0.16 0.12 8.80 0.36 0.21 0.33 0.32 SEQID-03479 0.03 0.000.06 0.02 0.05 0.06 0.04 0.05 −23.08 0.39 0.01 8.46 0.30 0.35 0.23 0.00SEQID-03480 0.03 0.02 0.03 0.04 0.02 0.05 0.04 0.03 −25.60 0.37 0.1210.07 0.25 0.30 0.25 0.28 SEQID-03481 0.01 0.09 0.03 0.05 0.06 0.05 0.050.04 −23.17 0.35 −0.04 5.01 0.20 0.32 0.21 0.00 SEQID-03482 0.04 0.030.06 0.05 0.05 0.02 0.03 0.06 −24.86 0.31 0.01 8.90 0.25 0.33 0.00 0.00SEQID-03483 0.02 0.07 0.02 0.03 0.03 0.03 0.01 0.03 −24.64 0.35 0.049.80 0.25 0.32 0.00 0.19 SEQID-03484 0.04 0.06 0.04 0.04 0.07 0.02 0.020.03 −22.32 0.36 0.18 11.65 0.24 0.28 0.00 0.27 SEQID-03485 0.04 0.050.06 0.07 0.07 0.00 0.02 0.04 −20.22 0.48 0.00 6.06 0.19 0.35 0.00 0.00SEQID-03486 0.05 0.01 0.00 0.05 0.09 0.04 0.06 0.07 −21.49 0.30 0.2111.05 0.19 0.28 0.28 0.24 SEQID-03487 0.11 0.032 0.04 0.05 0.09 0.010.01 0.04 −22.55 0.26 0.10 12.41 0.23 0.37 0.22 0.00 SEQID-03488 0.050.03 0.01 0.04 0.09 0.01 0.01 0.06 −22.64 0.42 −0.06 4.32 0.22 0.29 0.220.22 SEQID-03489 0.01 0.02 0.04 0.02 0.09 0.05 0.01 0.02 −27.29 0.110.14 10.34 0.22 0.30 0.26 0.25 SEQID-03490 0.03 0.06 0.02 0.05 0.05 0.000.07 0.05 −25.31 0.43 −0.02 5.41 0.22 0.34 0.00 0.00 SEQID-03491 0.010.03 0.02 0.07 0.05 0.01 0.03 0.03 −24.17 0.20 −0.03 5.20 0.23 0.32 0.000.25 SEQID-03492 0.07 0.03 0.03 0.02 0.11 0.01 0.05 0.03 −20.36 0.490.09 10.76 0.23 0.30 0.18 0.26 SEQID-03493 0.02 0.07 0.02 0.10 0.06 0.060.03 0.05 −23.62 0.33 0.31 12.73 0.35 0.34 0.29 0.24 SEQID-03494 0.040.04 0.02 0.05 0.08 0.01 0.05 0.04 −20.69 0.48 0.00 7.29 0.21 0.31 0.220.24 SEQID-03495 0.02 0.00 0.06 0.08 0.06 0.00 0.00 0.01 −23.02 0.18−0.05 4.51 0.28 0.24 0.33 0.30 SEQID-03496 0.03 0.04 0.01 0.07 0.03 0.020.01 0.03 −34.51 0.02 0.15 10.95 0.27 0.31 0.00 0.28 SEQID-03497 0.010.06 0.02 0.06 0.05 0.02 0.02 0.03 −23.27 0.32 0.04 10.07 0.21 0.33 0.000.00 SEQID-03498 0.02 0.00 0.05 0.05 0.08 0.01 0.06 0.05 −28.10 0.22−0.10 4.15 0.27 0.32 0.27 0.00 SEQID-03499 0.03 0.10 0.05 0.08 0.03 0.000.04 0.03 −20.87 0.44 0.14 11.02 0.25 0.31 0.25 0.23 SEQID-03500 0.010.05 0.01 0.04 0.07 0.01 0.08 0.04 −20.42 0.41 −0.08 4.18 0.00 0.33 0.000.00 SEQID-03501 0.02 0.05 0.04 0.05 0.03 0.01 0.09 0.04 −34.30 0.200.02 9.53 0.25 0.32 0.21 0.26 SEQID-03502 0.02 0.04 0.05 0.05 0.02 0.010.04 0.04 −37.06 0.18 −0.03 4.96 0.24 0.31 0.21 0.26 SEQID-03503 0.010.01 0.01 0.08 0.03 0.02 0.06 0.04 −21.65 0.32 0.13 11.37 0.28 0.30 0.000.26 SEQID-03504 0.04 0.00 0.03 0.09 0.05 0.00 0.03 0.09 −21.49 0.33−0.07 4.18 0.28 0.22 0.33 0.28 SEQID-03505 0.02 0.05 0.03 0.06 0.09 0.020.06 0.03 −23.32 0.27 −0.02 6.29 0.22 0.32 0.00 0.00 SEQID-03506 0.040.01 0.01 0.05 0.07 0.01 0.05 0.05 −25.65 0.19 0.04 9.69 0.27 0.30 0.000.26 SEQID-03507 0.03 0.06 0.04 0.06 0.04 0.01 0.05 0.03 −20.67 0.370.00 6.69 0.18 0.33 0.00 0.20 SEQID-03508 0.03 0.02 0.02 0.01 0.02 0.010.05 0.06 −31.80 0.29 −0.04 4.84 0.21 0.30 0.20 0.00 SEQID-03509 0.020.02 0.04 0.06 0.05 0.03 0.04 0.04 −21.76 0.32 −0.01 5.87 0.21 0.33 0.220.25 SEQID-03510 0.01 0.06 0.03 0.06 0.08 0.01 0.04 0.04 −20.40 0.31−0.03 4.96 0.20 0.31 0.00 0.20 SEQID-03511 0.02 0.04 0.02 0.06 0.04 0.030.01 0.02 −34.54 0.18 0.11 10.66 0.23 0.32 0.00 0.22 SEQID-03512 0.060.03 0.03 0.03 0.07 0.00 0.03 0.08 −21.60 0.44 0.14 11.38 0.22 0.30 0.000.21 SEQID-03513 0.01 0.07 0.03 0.03 0.04 0.02 0.04 0.06 −22.41 0.48−0.01 6.17 0.24 0.34 0.24 0.00 SEQID-03514 0.02 0.00 0.06 0.08 0.06 0.000.00 0.01 −23.02 0.22 −0.05 4.51 0.29 0.25 0.33 0.31 SEQID-03515 0.050.04 0.05 0.04 0.09 0.02 0.09 0.06 −22.65 0.33 0.11 10.98 0.23 0.28 0.000.00 SEQID-03516 0.03 0.04 0.01 0.07 0.03 0.01 0.06 0.06 −22.44 0.280.06 10.10 0.00 0.33 0.00 0.00 SEQID-03517 0.02 0.07 0.02 0.11 0.05 0.060.03 0.03 −23.64 0.23 0.31 12.59 0.31 0.20 0.26 0.29 SEQID-03518 0.020.06 0.032 0.03 0.03 0.02 0.02 0.03 −25.15 0.34 0.03 9.43 0.25 0.31 0.230.21 SEQID-03519 0.03 0.03 0.03 0.02 0.04 0.00 0.02 0.09 −22.86 0.50−0.02 5.88 0.19 0.31 0.00 0.22 SEQID-03520 0.01 0.00 0.11 0.023 0.010.00 0.00 0.02 −33.31 0.00 0.13 10.79 0.31 0.32 0.29 0.31 SEQID-035210.01 0.09 0.05 0.01 0.02 0.02 0.03 0.14 −24.48 0.31 −0.02 5.75 0.27 0.300.00 0.26 SEQID-03522 0.01 0.06 0.07 0.03 0.04 0.01 0.04 0.02 −20.660.12 0.13 11.83 0.25 0.33 0.00 0.28 SEQID-03523 0.03 0.09 0.06 0.05 0.040.04 0.03 0.02 −20.10 0.31 0.06 8.20 0.33 0.19 0.33 0.31 SEQID-035240.07 0.03 0.02 0.01 0.04 0.02 0.08 0.03 −28.01 0.20 0.13 10.72 0.25 0.270.00 0.25 SEQID-03525 0.01 0.06 0.06 0.09 0.04 0.01 0.03 0.03 −21.420.14 0.13 11.89 0.28 0.33 0.00 0.27 SEQID-03526 0.03 0.06 0.02 0.03 0.040.02 0.02 0.05 −23.48 0.35 0.01 7.23 0.25 0.31 0.22 0.22 SEQID-035270.05 0.05 0.05 0.01 0.01 0.01 0.06 0.04 −29.27 0.21 0.02 8.32 0.22 0.300.24 0.24 SEQID-03528 0.02 0.03 0.03 0.03 0.05 0.01 0.02 0.07 −21.600.44 −0.02 6.04 0.20 0.32 0.24 0.00 SEQID-03529 0.03 0.02 0.03 0.05 0.030.01 0.06 0.09 −23.91 0.47 0.05 10.14 0.24 0.31 0.00 0.00 SEQID-035300.01 0.03 0.01 0.10 0.03 0.03 0.02 0.03 −34.65 0.13 0.16 10.91 0.23 0.330.24 0.25 SEQID-03531 0.02 0.02 0.01 0.06 0.06 0.05 0.00 0.07 −23.630.20 0.24 12.74 0.30 0.23 0.00 0.30 SEQID-03532 0.03 0.02 0.02 0.03 0.060.00 0.02 0.08 −23.72 0.40 −0.02 6.25 0.30 0.29 0.00 0.29 SEQID-035330.03 0.02 0.02 0.01 0.03 0.01 0.06 0.04 −26.72 0.24 0.11 10.79 0.23 0.290.24 0.25 SEQID-03534 0.02 0.07 0.03 0.06 0.04 0.02 0.05 0.05 −27.540.31 −0.26 3.23 0.25 0.30 0.00 0.24 SEQID-03535 0.03 0.05 0.01 0.04 0.040.01 0.07 0.06 −21.01 0.48 0.04 9.70 0.00 0.30 0.20 0.00 SEQID-035360.01 0.04 0.02 0.04 0.05 0.00 0.03 0.08 −20.34 0.46 0.00 6.82 0.22 0.320.00 0.00 SEQID-03537 0.02 0.06 0.01 0.07 0.04 0.02 0.06 0.07 −27.330.33 −0.24 3.35 0.27 0.31 0.24 0.26 SEQID-03538 0.05 0.04 0.04 0.02 0.060.00 0.06 0.10 −23.10 0.36 0.02 8.98 0.27 0.24 0.00 0.27 SEQID-035390.00 0.089 0.04 0.04 0.04 0.01 0.04 0.09 −20.60 0.47 −0.01 6.61 0.210.31 0.00 0.22 SEQID-03540 0.02 0.07 0.01 0.06 0.04 0.02 0.04 0.06−30.13 0.36 −0.29 3.26 0.29 0.32 0.23 0.24 SEQID-03541 0.03 0.06 0.040.09 0.03 0.03 0.02 0.02 −20.94 0.29 0.04 10.11 0.22 0.33 0.00 0.22SEQID-03542 0.03 0.01 0.05 0.04 0.02 0.01 0.02 0.10 −22.09 0.50 −0.025.44 0.22 0.31 0.20 0.22 SEQID-03543 0.04 0.05 0.01 0.04 0.03 0.02 0.030.04 −37.89 0.20 −0.30 3.53 0.23 0.31 0.00 0.22 SEQID-03544 0.02 0.090.03 0.03 0.06 0.01 0.04 0.09 −26.74 0.38 0.17 11.00 0.24 0.30 0.23 0.29SEQID-03545 0.04 0.06 0.04 0.11 0.03 0.03 0.05 0.03 −24.11 0.18 0.2712.15 0.31 0.23 0.00 0.27 SEQID-03546 0.05 0.03 0.03 0.05 0.04 0.01 0.060.03 −24.14 0.36 0.01 8.21 0.18 0.29 0.25 0.25 SEQID-03547 0.01 0.050.01 0.09 0.04 0.01 0.05 0.02 −20.44 0.34 −0.07 4.32 0.24 0.33 0.25 0.21SEQID-03548 0.02 0.05 0.03 0.03 0.01 0.02 0.03 0.06 −24.19 0.35 0.098.87 0.20 0.30 0.28 0.29 SEQID-03549 0.01 0.06 0.05 0.04 0.05 0.01 0.050.04 −21.47 0.39 −0.01 5.98 0.23 0.34 0.00 0.25 SEQID-03550 0.04 0.030.03 0.04 0.04 0.08 0.00 0.05 −22.98 0.25 −0.03 5.60 0.24 0.26 0.23 0.22SEQID-03551 0.01 0.04 0.03 0.02 0.00 0.00 0.07 0.02 −30.43 0.46 0.3812.96 0.25 0.28 0.24 0.21 SEQID-03552 0.05 0.05 0.04 0.03 0.06 0.03 0.060.00 −21.47 0.39 −0.01 6.51 0.22 0.12 0.26 0.31 SEQID-03553 0.03 0.030.02 0.03 0.05 0.01 0.04 0.04 −23.53 0.48 0.13 11.75 0.22 0.30 0.00 0.24SEQID-03554 0.03 0.03 0.00 0.06 0.04 0.01 0.07 0.04 −22.98 0.39 0.2312.48 0.21 0.29 0.00 0.23 SEQID-03555 0.03 0.09 0.01 0.03 0.01 0.11 0.010.04 −33.41 0.19 −0.02 5.58 0.21 0.34 0.19 0.00 SEQID-03556 0.05 0.060.02 0.02 0.03 0.01 0.05 0.04 −21.03 0.45 0.02 7.83 0.19 0.29 0.25 0.26SEQID-03557 0.08 0.06 0.05 0.04 0.03 0.01 0.03 0.07 −20.34 0.44 −0.016.51 0.21 0.33 0.00 0.23 SEQID-03558 0.02 0.13 0.01 0.06 0.05 0.01 0.040.04 −20.27 0.31 0.01 8.43 0.21 0.31 0.26 0.25 SEQID-03559 0.01 0.050.02 0.07 0.05 0.01 0.04 0.04 −21.00 0.47 −0.02 5.09 0.19 0.35 0.00 0.20SEQID-03560 0.02 0.04 0.00 0.05 0.05 0.01 0.07 0.01 −21.98 0.35 0.2112.36 0.25 0.27 0.25 0.23 SEQID-03561 0.08 0.03 0.07 0.06 0.03 0.02 0.050.04 −23.21 0.17 0.05 8.98 0.24 0.25 0.26 0.27 SEQID-03562 0.03 0.050.04 0.04 0.04 0.00 0.09 0.07 −20.11 0.48 −0.01 5.42 0.24 0.32 0.00 0.24SEQID-03563 0.02 0.04 0.03 0.09 0.10 0.05 0.00 0.10 −21.01 0.16 0.2312.72 0.28 0.21 0.00 0.31 SEQID-03564 0.04 0.05 0.01 0.04 0.03 0.02 0.030.04 −37.86 0.21 −0.30 3.53 0.22 0.31 0.00 0.22 SEQID-03565 0.01 0.070.03 0.05 0.04 0.02 0.06 0.02 −23.04 0.33 0.01 7.44 0.24 0.30 0.23 0.21SEQID-03566 0.04 0.05 0.02 0.02 0.03 0.01 0.07 0.04 −21.55 0.44 0.048.27 0.25 0.30 0.24 0.25 SEQID-03567 0.01 0.04 0.06 0.04 0.06 0.02 0.030.04 −22.19 0.29 −0.09 4.12 0.21 0.31 0.26 0.24 SEQID-03568 0.02 0.030.00 0.06 0.04 0.01 0.06 0.03 −24.22 0.38 0.24 12.55 0.23 0.29 0.00 0.22SEQID-03569 0.03 0.05 0.05 0.01 0.06 0.03 0.07 0.05 −21.51 0.27 0.027.62 0.26 0.28 0.26 0.27 SEQID-03570 0.04 0.04 0.04 0.05 0.08 0.02 0.020.03 −21.28 0.35 0.11 11.14 0.24 0.28 0.00 0.27 SEQID-03571 0.02 0.000.07 0.09 0.06 0.00 0.00 0.01 −23.06 0.21 −0.05 4.50 0.30 0.25 0.33 0.33SEQID-03572 0.02 0.02 0.06 0.04 0.03 0.01 0.02 0.06 −24.00 0.34 0.006.80 0.22 0.30 0.00 0.21 SEQID-03573 0.06 0.00 0.02 0.03 0.04 0.04 0.010.05 −33.26 0.16 0.18 11.10 0.30 0.32 0.25 0.23 SEQID-03574 0.02 0.090.03 0.06 0.04 0.02 0.07 0.03 −22.16 0.27 0.02 7.57 0.21 0.33 0.23 0.24SEQID-03575 0.09 0.04 0.01 0.02 0.02 0.03 0.04 0.03 −23.30 0.22 0.0610.14 0.22 0.29 0.28 0.24 SEQID-03576 0.00 0.03 0.03 0.09 0.05 0.08 0.030.07 −20.50 0.40 −0.06 4.47 0.21 0.32 0.00 0.22 SEQID-03577 0.04 0.040.04 0.04 0.07 0.03 0.02 0.03 −21.01 0.39 0.13 11.51 0.28 0.31 0.00 0.28SEQID-03578 0.03 0.00 0.02 0.04 0.00 0.00 0.00 0.04 −30.44 0.26 0.3512.51 0.34 0.16 0.29 0.30 SEQID-03579 0.07 0.01 0.06 0.05 0.04 0.02 0.060.01 −22.91 0.12 −0.03 5.10 0.25 0.29 0.23 0.25 SEQID-03580 0.06 0.070.04 0.06 0.04 0.00 0.11 0.07 −20.66 0.47 0.16 10.79 0.31 0.15 0.29 0.32SEQID-03581 0.01 0.00 0.04 0.06 0.06 0.00 0.00 0.04 −31.33 0.10 0.2811.81 0.24 0.29 0.00 0.25 SEQID-03582 0.02 0.05 0.02 0.13 0.08 0.00 0.000.03 −21.40 0.48 0.15 12.39 0.26 0.17 0.00 0.28 SEQID-03583 0.04 0.050.05 0.04 0.00 0.15 0.00 0.00 −21.55 0.34 0.10 11.60 0.28 0.17 0.31 0.31SEQID-03584 0.12 0.00 0.00 0.10 0.08 0.04 0.09 0.02 −21.49 0.40 −0.064.43 0.30 0.17 0.29 0.00 SEQID-03585 0.01 0.01 0.08 0.03 0.03 0.06 0.040.03 −24.54 0.11 0.00 6.92 0.28 0.30 0.25 0.30 SEQID-03586 0.01 0.030.02 0.06 0.03 0.01 0.05 0.02 −24.37 0.12 0.02 7.74 0.24 0.30 0.27 0.26SEQID-03587 0.01 0.00 0.03 0.03 0.06 0.02 0.01 0.05 −26.49 0.18 0.0810.72 0.23 0.32 0.27 0.00 SEQID-03588 0.03 0.02 0.00 0.01 0.06 0.04 0.080.07 −24.87 0.30 0.03 8.70 0.24 0.22 0.00 0.00 SEQID-03589 0.08 0.020.04 0.03 0.02 0.02 0.08 0.07 −21.33 0.38 −0.07 4.34 0.25 0.28 0.00 0.00SEQID-03590 0.05 0.04 0.04 0.08 0.08 0.02 0.02 0.03 −22.89 0.36 0.0910.89 0.24 0.28 0.00 0.26 SEQID-03591 0.05 0.02 0.04 0.02 0.03 0.02 0.030.05 −21.51 0.26 0.08 10.64 0.26 0.33 0.20 0.28 SEQID-03592 0.01 0.020.02 0.05 0.05 0.03 0.09 0.06 −25.97 0.21 0.14 10.63 0.22 0.32 0.00 0.19SEQID-03593 0.06 0.00 0.02 0.04 0.00 0.00 0.00 0.02 −30.48 0.37 0.3512.51 0.29 0.14 0.29 0.29 SEQID-03594 0.09 0.02 0.03 0.05 0.03 0.01 0.010.06 −28.02 0.34 −0.03 4.85 0.23 0.32 0.00 0.00 SEQID-03595 0.04 0.020.07 0.05 0.03 0.01 0.02 0.02 −24.47 0.12 0.26 12.35 0.23 0.34 0.23 0.26SEQID-03596 0.09 0.03 0.04 0.05 0.03 0.04 0.00 0.04 −22.88 0.26 0.0810.76 0.27 0.27 0.27 0.24 SEQID-03597 0.02 0.03 0.03 0.03 0.04 0.00 0.030.07 −25.68 0.39 −0.04 4.87 0.26 0.30 0.24 0.25 SEQID-03598 0.01 0.040.05 0.05 0.04 0.04 0.03 0.05 −20.75 0.41 −0.03 5.31 0.21 0.33 0.20 0.21SEQID-03599 0.02 0.04 0.04 0.07 0.06 0.00 0.02 0.04 −20.97 0.39 0.029.10 0.21 0.33 0.00 0.21 SEQID-03600 0.03 0.06 0.04 0.03 0.06 0.01 0.050.05 −22.46 0.32 −0.03 5.03 0.20 0.30 0.24 0.00 SEQID-03601 0.02 0.020.04 0.05 0.09 0.05 0.02 0.10 −24.18 0.14 0.25 12.31 0.27 0.21 0.30 0.30SEQID-03602 0.01 0.04 0.04 0.04 0.08 0.03 0.03 0.06 −23.47 0.28 −0.035.59 0.22 0.31 0.22 0.20 SEQID-03603 0.02 0.04 0.02 0.05 0.04 0.00 0.030.08 −22.08 0.46 0.00 6.71 0.20 0.31 0.00 0.00 SEQID-03604 0.02 0.050.01 0.05 0.04 0.02 0.07 0.07 −27.64 0.33 −0.24 3.42 0.00 0.29 0.29 0.00SEQID-03605 0.05 0.04 0.04 0.02 0.06 0.00 0.06 0.10 −23.12 0.36 0.028.98 0.25 0.23 0.00 0.30 SEQID-03606 0.02 0.02 0.01 0.06 0.04 0.00 0.000.17 −25.73 0.39 0.15 10.95 0.29 0.28 0.22 0.28 SEQID-03607 0.03 0.040.02 0.05 0.02 0.02 0.05 0.04 −36.23 0.21 −0.26 3.59 0.22 0.31 0.23 0.22SEQID-03608 0.01 0.04 0.03 0.05 0.07 0.03 0.04 0.06 −23.92 0.27 −0.026.15 0.00 0.32 0.00 0.24 SEQID-03609 0.05 0.00 0.03 0.03 0.02 0.04 0.010.04 −32.73 0.18 0.19 11.18 0.25 0.32 0.23 0.00 SEQID-03610 0.02 0.050.03 0.06 0.04 0.01 0.11 0.03 −22.40 0.17 0.00 7.41 0.21 0.34 0.21 0.23SEQID-03611 0.01 0.00 0.10 0.04 0.08 0.00 0.00 0.02 −33.57 0.01 0.0910.58 0.29 0.33 0.26 0.32 SEQID-03612 0.01 0.02 0.05 0.01 0.02 0.01 0.080.07 −22.57 0.29 0.032 8.10 0.28 0.30 0.00 0.00 SEQID-03613 0.09 0.030.04 0.07 0.02 0.04 0.00 0.06 −23.00 0.27 0.09 10.90 0.28 0.28 0.23 0.24SEQID-03614 0.04 0.04 0.01 0.09 0.03 0.01 0.05 0.05 −18.44 0.28 0.018.63 0.68 0.38 0.21 0.21 SEQID-03615 0.01 0.01 0.04 0.04 0.03 0.01 0.040.06 −28.73 0.25 0.15 10.85 0.23 0.34 0.24 0.00 SEQID-03616 0.02 0.020.01 0.04 0.02 0.00 0.06 0.12 −23.86 0.38 −0.01 6.51 0.00 0.00 0.26 0.27SEQID-03617 0.02 0.04 0.10 0.02 0.02 0.01 0.05 0.03 −21.83 0.41 0.1512.23 0.28 0.31 0.28 0.28 SEQID-03618 0.03 0.02 0.05 0.03 0.05 0.01 0.020.08 −20.99 0.50 0.00 6.97 0.21 0.34 0.00 0.24 SEQID-03619 0.01 0.040.02 0.04 0.04 0.00 0.03 0.08 −20.098 0.47 0.00 7.10 0.22 0.35 0.23 0.00SEQID-03620 0.02 0.05 0.01 0.04 0.01 0.01 0.07 0.06 −21.54 0.48 0.049.69 0.00 0.31 0.00 0.00 SEQID-03621 0.03 0.05 0.02 0.04 0.01 0.02 0.030.04 −35.16 0.19 −0.27 3.58 0.25 0.31 0.00 0.22 SEQID-03622 0.04 0.040.03 0.10 0.03 0.02 0.05 0.06 −20.52 0.33 0.02 8.89 0.00 0.33 0.24 0.24SEQID-03623 0.01 0.03 0.01 0.09 0.03 0.02 0.05 0.04 −22.33 0.41 0.1411.77 0.32 0.32 0.00 0.24 SEQID-03624 0.04 0.08 0.02 0.03 0.04 0.02 0.040.04 −25.73 0.39 −0.25 3.16 0.24 0.29 0.00 0.25 SEQID-03625 0.02 0.120.02 0.01 0.04 0.03 0.03 0.04 −22.01 0.50 −0.04 1.68 0.25 0.32 0.24 0.25SEQID-03626 0.02 0.04 0.01 0.04 0.02 0.00 0.13 0.04 −24.81 0.22 −0.074.54 0.22 0.30 0.00 0.24 SEQID-03627 0.032 0.02 0.01 0.06 0.07 0.05 0.020.10 −23.81 0.15 0.24 12.43 0.31 0.24 0.00 0.26 SEQID-03628 0.02 0.030.01 0.11 0.09 0.02 0.06 0.06 −20.14 0.29 0.08 10.41 0.24 0.33 0.00 0.00SEQID-03629 0.02 0.02 0.03 0.04 0.03 0.00 0.00 0.09 −21.66 0.47 0.1111.35 0.31 0.23 0.26 0.00 SEQID-03630 0.02 0.04 0.02 0.05 0.03 0.02 0.050.04 −35.69 0.23 −0.29 3.45 0.20 0.30 0.24 0.21 SEQID-03631 0.05 0.070.03 0.05 0.05 0.02 0.05 0.06 −19.72 0.34 −0.06 4.46 0.40 0.54 0.00 0.22SEQID-03632 0.02 0.02 0.02 0.04 0.05 0.01 0.01 0.02 −20.44 0.47 0.027.98 0.22 0.33 0.23 0.28 SEQID-03633 0.01 0.02 0.06 0.09 0.05 0.01 0.020.06 −27.34 0.22 −0.06 4.54 0.22 0.33 0.24 0.25 SEQID-03634 0.04 0.010.05 0.05 0.06 0.01 0.04 0.06 −17.51 0.47 −0.01 6.05 0.20 0.33 0.00 0.20SEQID-03635 0.02 0.00 0.03 0.08 0.05 0.13 0.00 0.04 −23.52 0.09 0.129.75 0.27 0.18 0.33 0.33 SEQID-03636 0.03 0.07 0.00 0.10 0.04 0.04 0.040.09 −20.21 0.35 0.15 11.00 0.33 0.18 0.30 0.31 SEQID-03637 0.03 0.040.05 0.09 0.05 0.01 0.03 0.04 −21.12 0.13 0.02 7.73 0.20 0.33 0.00 0.00SEQID-03638 0.03 0.04 0.05 0.09 0.05 0.01 0.03 0.04 −21.08 0.13 0.027.72 0.21 0.33 0.00 0.20 SEQID-03639 0.08 0.04 0.04 0.04 0.04 0.06 0.070.06 −20.76 0.41 0.02 9.59 0.23 0.31 0.21 0.00 SEQID-03640 0.02 0.040.05 0.09 0.05 0.01 0.02 0.04 −29.86 0.19 −0.08 4.39 0.22 0.34 0.00 0.23SEQID-03641 0.01 0.02 0.20 0.04 0.03 0.01 0.02 0.03 −14.62 0.15 0.007.76 0.59 0.30 0.20 0.39 SEQID-03642 0.02 0.03 0.08 0.12 0.06 0.01 0.020.04 −20.93 0.21 0.00 7.12 0.18 0.38 0.19 0.19 SEQID-03643 0.02 0.000.02 0.02 0.04 0.00 0.00 0.15 −27.81 0.37 0.11 11.10 0.00 0.32 0.00 0.20SEQID-03644 0.06 0.00 0.04 0.04 0.00 0.00 0.00 0.14 −23.87 0.48 0.2512.14 0.29 0.13 0.32 0.33 SEQID-03645 0.01 0.01 0.03 0.00 0.089 0.000.05 0.03 −27.88 0.26 0.12 11.11 0.23 0.30 0.26 0.23 SEQID-03646 0.010.00 0.00 0.04 0.03 0.00 0.02 0.09 −21.23 0.40 0.16 11.45 0.29 0.30 0.000.30 SEQID-03647 0.09 0.00 0.01 0.09 0.04 0.00 0.00 0.04 −24.81 0.150.23 12.43 0.30 0.24 0.00 0.26 SEQID-03648 0.04 0.02 0.04 0.02 0.01 0.000.00 0.00 −36.23 0.05 0.17 10.80 0.31 0.25 0.29 0.31 SEQID-03649 0.000.04 0.02 0.09 0.11 0.03 0.04 0.06 −17.45 0.28 0.00 6.65 0.27 0.41 0.230.21 SEQID-03650 0.02 0.03 0.05 0.05 0.07 0.06 0.07 0.06 −18.43 0.31−0.03 4.61 0.22 0.33 0.21 0.21 SEQID-03651 0.01 0.01 0.05 0.00 0.01 0.050.14 0.05 −28.98 0.24 −0.15 3.67 0.44 0.51 0.23 0.21 SEQID-03652 0.040.02 0.00 0.06 0.04 0.00 0.05 0.07 −24.65 0.29 −0.04 5.01 0.27 0.22 0.320.31 SEQID-03653 0.03 0.01 0.00 0.06 0.11 0.00 0.02 0.03 −25.79 0.150.00 6.98 0.23 0.34 0.27 0.25 SEQID-03654 0.04 0.02 0.00 0.06 0.04 0.000.05 0.07 −24.44 0.29 −0.05 4.69 0.29 0.23 0.32 0.29 SEQID-03655 0.020.04 0.02 0.02 0.04 0.03 0.05 0.04 −21.52 0.40 0.09 10.57 0.21 0.32 0.000.23 SEQID-03656 0.02 0.12 0.02 0.08 0.07 0.03 0.05 0.02 −20.58 0.350.26 11.66 0.27 0.18 0.30 0.22 SEQID-03657 0.01 0.08 0.03 0.07 0.03 0.000.05 0.03 −22.79 0.22 0.15 11.36 0.27 0.30 0.27 0.00 SEQID-03658 0.030.03 0.13 0.08 0.05 0.02 0.02 0.03 −24.82 0.20 −0.01 5.98 0.23 0.33 0.220.25 SEQID-03659 0.01 0.098 0.01 0.04 0.04 0.00 0.14 0.03 −25.61 0.250.11 10.02 0.22 0.28 0.20 0.24 SEQID-03660 0.07 0.10 0.03 0.06 0.05 0.000.02 0.01 −26.25 0.07 0.31 12.76 0.26 0.21 0.00 0.28 SEQID-03661 0.090.00 0.04 0.04 0.00 0.00 0.00 0.11 −26.24 0.39 0.29 11.49 0.32 0.15 0.330.32 SEQID-03662 0.03 0.08 0.04 0.06 0.07 0.02 0.05 0.08 −24.61 0.250.10 10.56 0.26 0.32 0.30 0.00 SEQID-03663 0.01 0.05 0.06 0.02 0.06 0.000.01 0.04 −20.55 0.45 −0.04 4.54 0.30 0.32 0.26 0.26 SEQID-03664 0.050.03 0.04 0.07 0.03 0.00 0.02 0.01 −35.30 0.23 −0.28 3.63 0.28 0.31 0.250.24 SEQID-03665 0.01 0.05 0.00 0.05 0.05 0.00 0.05 0.04 −27.65 0.270.15 10.99 0.27 0.30 0.00 0.24 SEQID-03666 0.01 0.07 0.03 0.04 0.02 0.010.04 0.04 −23.16 0.37 0.01 8.05 0.44 0.59 0.00 0.21 SEQID-03667 0.010.08 0.00 0.09 0.02 0.00 0.04 0.03 −26.95 0.21 0.17 11.40 0.28 0.28 0.000.26 SEQID-03668 0.01 0.04 0.02 0.05 0.04 0.00 0.00 0.09 −25.82 0.49−0.08 4.18 0.28 0.33 0.26 0.27 SEQID-03669 0.03 0.07 0.02 0.02 0.07 0.000.10 0.05 −25.38 0.28 −0.07 4.41 0.27 0.23 0.00 0.18 SEQID-03670 0.040.03 0.03 0.05 0.00 0.02 0.06 0.03 −28.28 0.10 0.22 11.46 0.27 0.28 0.000.28 SEQID-03671 0.06 0.04 0.03 0.03 0.06 0.00 0.09 0.05 −23.14 0.15−0.04 4.59 0.26 0.30 0.19 0.00 SEQID-03672 0.02 0.11 0.06 0.01 0.06 0.000.02 0.05 −24.34 0.38 0.22 11.00 0.30 0.25 0.29 0.00 SEQID-03673 0.030.03 0.00 0.07 0.07 0.00 0.06 0.03 −22.85 0.16 0.20 11.53 0.25 0.23 0.280.28 SEQID-03674 0.02 0.00 0.02 0.04 0.06 0.00 0.00 0.14 −25.40 0.340.11 11.18 0.00 0.31 0.00 0.20 SEQID-03675 0.06 0.00 0.01 0.06 0.04 0.000.00 0.04 −26.36 0.07 0.22 12.05 0.25 0.20 0.00 0.30 SEQID-03676 0.020.04 0.03 0.04 0.08 0.00 0.02 0.04 −22.75 0.14 −0.22 3.08 0.33 0.28 0.000.00 SEQID-03677 0.07 0.04 0.01 0.04 0.07 0.02 0.05 0.04 −25.14 0.25−0.08 4.58 0.28 0.30 0.00 0.00 SEQID-03678 0.01 0.00 0.00 0.03 0.03 0.000.02 0.07 −20.36 0.41 0.14 11.42 0.28 0.30 0.00 0.26 SEQID-03679 0.020.02 0.02 0.06 0.05 0.09 0.08 0.09 −21.80 0.30 0.01 8.83 0.25 0.28 0.200.24 SEQID-03680 0.15 0.03 0.03 0.02 0.05 0.00 0.03 0.03 −24.71 0.20−0.04 4.53 0.22 0.29 0.22 0.23 SEQID-03681 0.08 0.06 0.01 0.03 0.04 0.000.05 0.03 −22.61 0.19 −0.05 4.29 0.23 0.31 0.00 0.00 SEQID-03682 0.010.00 0.00 0.03 0.03 0.00 0.02 0.07 −20.36 0.41 0.14 11.57 0.28 0.30 0.000.24 SEQID-03683 0.02 0.04 0.03 0.04 0.11 0.00 0.02 0.05 −22.90 0.13−0.22 3.08 0.32 0.27 0.00 0.00 SEQID-03684 0.04 0.03 0.08 0.02 0.08 0.000.02 0.08 −20.40 0.40 −0.14 3.73 0.28 0.31 0.00 0.22 SEQID-03685 0.090.00 0.01 0.02 0.07 0.00 0.00 0.04 −25.89 0.17 0.25 12.44 0.30 0.24 0.290.00 SEQID-03686 0.03 0.02 0.00 0.05 0.03 0.00 0.02 0.04 −22.07 0.360.17 11.95 0.26 0.29 0.00 0.23 SEQID-03687 0.07 0.06 0.02 0.05 0.04 0.000.00 0.02 −28.97 0.12 0.39 13.58 0.27 0.15 0.30 0.29 SEQID-03688 0.020.00 0.02 0.03 0.04 0.00 0.00 0.16 −27.06 0.42 0.12 11.21 0.24 0.31 0.000.00 SEQID-03689 0.01 0.03 0.03 0.07 0.08 0.01 0.11 0.07 −17.78 0.250.00 6.87 0.22 0.32 0.21 0.21 SEQID-03690 0.02 0.03 0.04 0.09 0.05 0.080.10 0.03 −15.75 0.26 0.00 6.53 0.00 0.33 0.00 0.22 SEQID-03691 0.020.03 0.00 0.05 0.06 0.01 0.07 0.06 −30.38 0.14 0.03 9.69 0.23 0.35 0.000.20 SEQID-03692 0.00 0.01 0.04 0.05 0.07 0.03 0.03 0.03 −19.20 0.260.00 8.72 0.00 0.36 0.00 0.20 SEQID-03693 0.05 0.05 0.05 0.07 0.05 0.010.05 0.02 −22.32 0.13 0.00 6.55 0.19 0.33 0.19 0.20 SEQID-03694 0.030.03 0.05 0.08 0.05 0.02 0.04 0.05 −26.41 0.21 0.05 10.06 0.20 0.33 0.000.21 SEQID-03695 0.02 0.04 0.05 0.04 0.06 0.03 0.01 0.05 −22.65 0.190.02 9.92 0.21 0.33 0.17 0.00 SEQID-03696 0.05 0.05 0.04 0.04 0.03 0.020.05 0.02 −31.03 0.20 0.03 9.50 0.21 0.31 0.18 0.23 SEQID-03697 0.050.02 0.00 0.03 0.04 0.00 0.00 0.07 −39.00 0.31 −0.28 3.65 0.26 0.34 0.230.28 SEQID-03698 0.13 0.00 0.00 0.03 0.03 0.00 0.00 0.03 −39.85 0.110.56 13.35 0.32 0.10 0.32 0.32 SEQID-03699 0.02 0.03 0.02 0.04 0.05 0.000.00 0.05 −34.84 0.17 −0.18 4.16 0.30 0.33 0.24 0.26 SEQID-03700 0.000.06 0.03 0.07 0.06 0.00 0.06 0.10 −24.50 0.40 −0.19 3.59 0.25 0.28 0.000.00 SEQID-03701 0.00 0.03 0.03 0.03 0.05 0.00 0.06 0.09 −23.52 0.270.00 7.53 0.35 0.22 0.00 0.00 SEQID-03702 0.00 0.03 0.05 0.05 0.05 0.000.06 0.09 −24.58 0.31 −0.02 4.92 0.33 0.20 0.00 0.31 SEQID-03703 0.000.03 0.05 0.03 0.05 0.00 0.06 0.09 −24.92 0.27 −0.02 5.78 0.36 0.22 0.000.27 SEQID-03704 0.02 0.02 0.00 0.03 0.04 0.00 0.05 0.03 −37.34 0.120.51 12.70 0.33 0.21 0.33 0.30 SEQID-03705 0.01 0.06 0.02 0.01 0.08 0.000.04 0.06 −26.05 0.18 0.26 11.32 0.22 0.31 0.25 0.21 SEQID-03706 0.010.08 0.04 0.07 0.02 0.00 0.02 0.03 −28.24 0.23 −0.08 4.34 0.34 0.34 0.270.28 SEQID-03707 0.00 0.03 0.07 0.07 0.06 0.00 0.02 0.03 −21.71 0.38−0.01 6.49 0.27 0.30 0.26 0.28 SEQID-03708 0.01 0.01 0.05 0.00 0.01 0.050.15 0.05 −29.44 0.24 −0.16 3.86 0.43 0.49 0.22 0.22 SEQID-03709 0.040.01 0.01 0.03 0.05 0.00 0.02 0.02 −28.31 0.07 −0.01 5.26 0.28 0.31 0.000.30 SEQID-03710 0.06 0.02 0.03 0.01 0.05 0.06 0.03 0.00 −25.89 0.070.13 13.06 0.31 0.20 0.00 0.00 SEQID-03711 0.02 0.02 0.04 0.03 0.06 0.000.05 0.01 −25.32 0.12 0.30 11.95 0.30 0.22 0.25 0.28 SEQID-03712 0.010.01 0.04 0.00 0.03 0.05 0.15 0.04 −30.09 0.32 −0.18 3.83 0.35 0.42 0.200.22 SEQID-03713 0.01 0.03 0.07 0.09 0.12 0.00 0.09 0.05 −24.01 0.27−0.03 4.92 0.20 0.31 0.00 0.25 SEQID-03714 0.02 0.06 0.04 0.08 0.06 0.010.02 0.02 −21.00 0.23 −0.04 4.70 0.20 0.33 0.20 0.20 SEQID-03715 0.050.02 0.02 0.04 0.09 0.00 0.08 0.01 −23.13 0.06 −0.01 6.12 0.25 0.34 0.240.27 SEQID-03716 0.00 0.05 0.12 0.00 0.00 0.00 0.12 0.02 −23.49 0.20−0.12 4.05 0.33 0.20 0.29 0.30 SEQID-03717 0.03 0.01 0.00 0.07 0.11 0.000.02 0.03 −25.89 0.15 −0.01 6.15 0.24 0.34 0.27 0.26 SEQID-03718 0.030.04 0.00 0.02 0.16 0.00 0.13 0.00 −20.29 0.17 0.12 10.45 0.30 0.12 0.290.00 SEQID-03719 0.02 0.08 0.00 0.03 0.05 0.03 0.09 0.07 −20.63 0.480.07 9.72 0.30 0.17 0.00 0.27 SEQID-03720 0.02 0.04 0.03 0.04 0.08 0.000.02 0.04 −22.75 0.15 −0.22 3.08 0.28 0.23 0.00 0.28 SEQID-03721 0.020.05 0.05 0.09 0.07 0.01 0.03 0.03 −20.94 0.13 −0.03 5.06 0.19 0.34 0.170.19 SEQID-03722 0.03 0.00 0.04 0.04 0.00 0.00 0.00 0.05 −26.69 0.470.30 12.31 0.32 0.15 0.32 0.32 SEQID-03723 0.02 0.03 0.03 0.08 0.04 0.000.04 0.05 −24.41 0.18 −0.07 4.67 0.18 0.33 0.18 0.21 SEQID-03724 0.020.03 0.01 0.07 0.07 0.00 0.03 0.02 −25.20 0.11 −0.10 4.27 0.20 0.28 0.240.20 SEQID-03725 0.00 0.05 0.04 0.05 0.03 0.00 0.089 0.07 −23.75 0.36−0.12 4.11 0.28 0.30 0.28 0.26 SEQID-03726 0.00 0.08 0.03 0.05 0.04 0.000.05 0.08 −22.85 0.43 −0.14 3.96 0.23 0.34 0.26 0.27 SEQID-03727 0.020.00 0.00 0.05 0.02 0.00 0.05 0.04 −39.39 0.04 0.54 12.73 0.38 0.24 0.320.28 SEQID-03728 0.04 0.01 0.01 0.05 0.04 0.00 0.02 0.02 −28.12 0.060.01 7.70 0.27 0.31 0.00 0.29 SEQID-03729 0.03 0.12 0.03 0.07 0.03 0.010.04 0.03 −20.53 0.38 0.05 10.07 0.22 0.28 0.00 0.22 SEQID-03730 0.000.05 0.04 0.07 0.09 0.03 0.08 0.07 −15.74 0.44 −0.04 4.58 0.22 0.33 0.000.00 SEQID-03731 0.01 0.00 0.03 0.04 0.02 0.00 0.04 0.03 −37.31 0.040.32 12.55 0.31 0.32 0.30 0.26 SEQID-03732 0.02 0.00 0.09 0.04 0.04 0.000.05 0.02 −28.34 0.06 0.25 12.48 0.27 0.31 0.31 0.27 SEQID-03733 0.010.10 0.04 0.07 0.06 0.00 0.05 0.10 −20.09 0.34 −0.09 4.15 0.27 0.32 0.250.26 SEQID-03734 0.00 0.02 0.02 0.11 0.05 0.00 0.03 0.02 −32.91 0.000.36 12.46 0.26 0.18 0.31 0.27 SEQID-03735 0.04 0.01 0.01 0.09 0.05 0.000.03 0.02 −28.66 0.08 −0.02 4.97 0.28 0.32 0.26 0.29 SEQID-03736 0.030.03 0.08 0.05 0.10 0.00 0.00 0.02 −32.42 0.06 −0.02 4.98 0.35 0.18 0.350.27 SEQID-03737 0.02 0.00 0.07 0.15 0.04 0.00 0.02 0.03 −23.09 0.010.25 12.40 0.26 0.34 0.28 0.25 SEQID-03738 0.13 0.06 0.03 0.07 0.03 0.000.08 0.02 −20.71 0.22 0.02 8.20 0.24 0.28 0.00 0.00 SEQID-03739 0.020.04 0.01 0.03 0.04 0.00 0.02 0.05 −24.16 0.40 0.00 6.97 0.27 0.32 0.250.24 SEQID-03740 0.02 0.07 0.01 0.09 0.05 0.06 0.05 0.03 −22.98 0.300.26 11.93 0.32 0.23 0.33 0.00 SEQID-03741 0.03 0.03 0.03 0.04 0.02 0.000.00 0.02 −35.11 0.12 −0.01 6.55 0.27 0.34 0.24 0.25 SEQID-03742 0.010.05 0.04 0.10 0.06 0.00 0.02 0.03 −21.70 0.23 −0.03 5.63 0.20 0.33 0.000.19 SEQID-03743 0.03 0.03 0.02 0.06 0.02 0.00 0.08 0.03 −23.45 0.220.18 11.09 0.23 0.26 0.21 0.22 SEQID-03744 0.02 0.03 0.01 0.01 0.00 0.000.093 0.05 −30.92 0.34 0.02 7.34 0.23 0.30 0.22 0.25 SEQID-03745 0.010.04 0.02 0.01 0.00 0.00 0.01 0.04 −30.77 0.31 0.12 10.52 0.20 0.27 0.000.26 SEQID-03746 0.08 0.03 0.03 0.08 0.05 0.00 0.05 0.02 −20.04 0.16−0.02 5.80 0.21 0.34 0.00 0.00 SEQID-03747 0.04 0.05 0.02 0.16 0.08 0.000.02 0.00 −23.42 0.21 0.01 8.483 0.24 0.31 0.00 0.25 SEQID-03748 0.010.08 0.04 0.14 0.05 0.00 0.05 0.02 −22.65 0.13 0.04 9.95 0.23 0.33 0.000.22 SEQID-03749 0.01 0.113 0.04 0.04 0.06 0.02 0.07 0.01 −23.48 0.16−0.08 4.43 0.26 0.24 0.31 0.28 SEQID-03750 0.02 0.08 0.07 0.07 0.10 0.000.07 0.03 −20.25 0.24 0.10 10.30 0.28 0.29 0.22 0.28 SEQID-03751 0.020.04 0.03 0.14 0.04 0.00 0.04 0.04 −25.76 0.34 0.16 10.96 0.32 0.28 0.000.25 SEQID-03752 0.05 0.01 0.01 0.07 0.05 0.00 0.02 0.02 −30.53 0.08−0.04 4.83 0.29 0.31 0.00 0.30 SEQID-03753 0.01 0.03 0.04 0.08 0.05 0.020.05 0.05 −23.34 0.34 0.14 11.07 0.00 0.30 0.25 0.20 SEQID-03754 0.030.02 0.01 0.07 0.07 0.00 0.02 0.04 −28.01 0.09 0.00 7.55 0.29 0.30 0.270.32 SEQID-03755 0.05 0.00 0.01 0.07 0.05 0.00 0.03 0.02 −27.72 0.07−0.01 5.27 0.29 0.31 0.24 0.30 SEQID-03756 0.02 0.02 0.14 0.06 0.02 0.030.01 0.05 −21.30 0.29 0.08 11.45 0.25 0.34 0.24 0.24 SEQID-03757 0.060.05 0.04 0.01 0.06 0.06 0.05 0.00 −28.84 0.08 0.34 12.70 0.27 0.17 0.240.29 SEQID-03758 0.01 0.06 0.05 0.03 0.03 0.04 0.05 0.04 −30.63 0.26−0.13 4.06 0.32 0.49 0.00 0.22 SEQID-03759 0.03 0.02 0.02 0.15 0.09 0.000.01 0.03 −22.70 0.32 0.08 11.04 0.25 0.30 0.00 0.22 SEQID-03760 0.010.03 0.03 0.12 0.08 0.03 0.06 0.09 −14.72 0.43 −0.03 4.43 0.22 0.41 0.000.23 SEQID-03761 0.02 0.14 0.05 0.04 0.04 0.03 0.08 0.03 −26.38 0.130.13 10.96 0.25 0.27 0.28 0.25 SEQID-03762 0.02 0.02 0.01 0.04 0.05 0.000.00 0.14 −26.13 0.39 0.13 10.85 0.27 0.26 0.32 0.29 SEQID-03763 0.010.00 0.07 0.00 0.02 0.05 0.16 0.04 −28.55 0.19 −0.16 3.84 0.47 0.53 0.210.24 SEQID-03764 0.05 0.03 0.06 0.07 0.06 0.00 0.00 0.00 −35.85 0.01−0.05 4.72 0.33 0.18 0.30 0.28 SEQID-03765 0.05 0.06 0.05 0.04 0.03 0.000.02 0.04 −21.74 0.44 0.02 8.22 0.33 0.29 0.24 0.00 SEQID-03766 0.050.03 0.04 0.05 0.10 0.00 0.00 0.00 −33.95 0.07 −0.02 5.02 0.27 0.15 0.330.33 SEQID-03767 0.02 0.02 0.00 0.03 0.04 0.00 0.05 0.04 −38.70 0.110.53 12.73 0.33 0.21 0.33 0.29 SEQID-03768 0.00 0.05 0.03 0.11 0.11 0.050.07 0.06 −15.13 0.40 −0.06 3.96 0.21 0.38 0.00 0.21 SEQID-03769 0.010.07 0.02 0.02 0.07 0.00 0.02 0.06 −26.47 0.34 −0.02 6.35 0.31 0.32 0.250.32 SEQID-03770 0.03 0.06 0.06 0.02 0.04 0.00 0.04 0.04 −21.97 0.500.04 9.61 0.27 0.23 0.32 0.00 SEQID-03771 0.00 0.05 0.12 0.00 0.00 0.030.11 0.03 −24.09 0.12 −0.11 4.21 0.33 0.20 0.29 0.33 SEQID-03772 0.000.05 0.12 0.00 0.00 0.00 0.12 0.04 −23.97 0.13 −0.11 4.21 0.33 0.20 0.350.35 SEQID-03773 0.00 0.07 0.03 0.03 0.07 0.00 0.06 0.03 −20.39 0.22−0.02 5.00 0.28 0.26 0.00 0.24 SEQID-03774 0.05 0.02 0.04 0.01 0.02 0.000.02 0.02 −36.47 0.14 −0.05 4.75 0.26 0.33 0.25 0.00 SEQID-03775 0.020.05 0.09 0.00 0.04 0.00 0.12 0.04 −23.92 0.09 −0.12 4.05 0.33 0.20 0.290.33 SEQID-03776 0.02 0.03 0.04 0.10 0.06 0.08 0.10 0.03 −15.43 0.250.00 6.53 0.19 0.33 0.00 0.21 SEQID-03777 0.07 0.02 0.01 0.01 0.14 0.000.02 0.02 −25.61 0.08 0.05 10.21 0.31 0.34 0.00 0.29 SEQID-03778 0.030.02 0.04 0.09 0.05 0.00 0.09 0.06 −22.47 0.20 −0.06 4.44 0.00 0.31 0.000.22 SEQID-03779 0.07 0.05 0.02 0.03 0.07 0.00 0.00 0.05 −31.12 0.150.38 13.11 0.30 0.17 0.30 0.33 SEQID-03780 0.04 0.03 0.04 0.05 0.00 0.020.05 0.05 −25.62 0.07 0.20 11.73 0.25 0.28 0.00 0.24 SEQID-03781 0.020.05 0.03 0.02 0.09 0.00 0.03 0.09 −23.27 0.32 0.17 10.49 0.30 0.18 0.290.30 SEQID-03782 0.08 0.06 0.01 0.03 0.04 0.00 0.05 0.03 −21.91 0.20−0.04 4.37 0.23 0.31 0.00 0.00 SEQID-03783 0.07 0.06 0.01 0.08 0.05 0.000.02 0.01 −26.74 0.11 0.32 12.83 0.24 0.20 0.00 0.27 SEQID-03784 0.020.04 0.01 0.04 0.05 0.00 0.14 0.04 −23.57 0.27 −0.08 4.60 0.28 0.33 0.000.25 SEQID-03785 0.01 0.08 0.01 0.02 0.06 0.04 0.09 0.06 −22.59 0.260.05 9.40 0.17 0.25 0.00 0.22 SEQID-03786 0.04 0.08 0.03 0.06 0.04 0.000.14 0.01 −23.30 0.15 −0.08 4.43 0.28 0.28 0.00 0.26 SEQID-03787 0.110.04 0.02 0.03 0.03 0.00 0.01 0.05 −23.23 0.25 −0.03 4.64 0.22 0.29 0.000.24 SEQID-03788 0.02 0.02 0.01 0.04 0.04 0.00 0.00 0.14 −26.07 0.390.13 10.85 0.27 0.26 0.31 0.29 SEQID-03789 0.02 0.08 0.04 0.06 0.09 0.020.03 0.08 −22.78 0.32 0.10 10.83 0.28 0.32 0.00 0.27 SEQID-03790 0.030.02 0.00 0.07 0.05 0.00 0.00 0.17 −22.17 0.45 0.10 10.80 0.25 0.24 0.000.19 SEQID-03791 0.03 0.13 0.03 0.06 0.05 0.00 0.07 0.04 −22.87 0.250.04 9.47 0.27 0.30 0.24 0.26 SEQID-03792 0.02 0.06 0.05 0.14 0.05 0.000.03 0.02 −20.96 0.15 0.04 10.05 0.23 0.33 0.00 0.20 SEQID-03793 0.010.04 0.01 0.01 0.02 0.00 0.02 0.02 −32.65 0.32 0.02 7.39 0.18 0.31 0.230.27 SEQID-03794 0.02 0.03 0.04 0.02 0.06 0.01 0.14 0.05 −22.93 0.220.03 9.12 0.23 0.30 0.21 0.00 SEQID-03795 0.02 0.08 0.02 0.07 0.07 0.060.03 0.02 −20.65 0.38 0.27 11.98 0.33 0.21 0.27 0.28 SEQID-03796 0.020.05 0.02 0.13 0.03 0.06 0.00 0.03 −23.50 0.29 0.31 13.02 0.26 0.18 0.280.32 SEQID-03797 0.01 0.01 0.07 0.08 0.07 0.00 0.02 0.06 −27.59 0.130.28 11.65 0.23 0.32 0.00 0.26 SEQID-03798 0.01 0.01 0.05 0.00 0.01 0.050.15 0.05 −28.97 0.24 −0.15 3.88 0.43 0.49 0.22 0.21 SEQID-03799 0.030.02 0.12 0.05 0.03 0.00 0.02 0.05 −21.47 0.18 0.03 9.78 0.26 0.30 0.270.29 SEQID-03800 0.02 0.03 0.16 0.09 0.05 0.01 0.01 0.04 −20.32 0.210.05 11.22 0.23 0.34 0.21 0.24 SEQID-03801 0.02 0.05 0.04 0.09 0.04 0.010.07 0.01 −20.88 0.15 0.03 9.74 0.21 0.33 0.00 0.21 SEQID-03802 0.040.02 0.07 0.04 0.06 0.00 0.05 0.10 −24.31 0.18 0.26 12.22 0.31 0.24 0.220.00 SEQID-03803 0.02 0.05 0.04 0.08 0.05 0.00 0.02 0.04 −21.78 0.200.04 10.22 0.21 0.31 0.00 0.20 SEQID-03804 0.04 0.06 0.03 0.06 0.04 0.000.00 0.03 −28.60 0.12 0.00 6.83 0.27 0.21 0.22 0.31 SEQID-03805 0.030.00 0.02 0.04 0.00 0.00 0.00 0.00 −28.57 0.42 0.33 12.42 0.34 0.16 0.340.30 SEQID-03806 0.01 0.04 0.03 0.04 0.04 0.00 0.07 0.16 −24.25 0.460.06 9.93 0.00 0.26 0.21 0.00 SEQID-03807 0.03 0.02 0.01 0.05 0.05 0.000.02 0.04 −23.55 0.21 0.16 11.44 0.27 0.28 0.00 0.31 SEQID-03808 0.030.02 0.00 0.07 0.05 0.00 0.00 0.17 −22.29 0.45 0.08 10.60 0.26 0.26 0.000.00 SEQID-03809 0.03 0.09 0.04 0.05 0.06 0.02 0.02 0.09 −24.75 0.350.10 10.81 0.23 0.28 0.00 0.28 SEQID-03810 0.02 0.05 0.13 0.05 0.02 0.010.03 0.05 −20.20 0.30 −0.02 5.86 0.20 0.34 0.22 0.23 SEQID-03811 0.050.00 0.03 0.08 0.03 0.00 0.00 0.03 −30.72 0.19 −0.15 4.15 0.31 0.33 0.250.28 SEQID-03812 0.06 0.04 0.10 0.07 0.00 0.01 0.01 0.03 −31.97 0.09−0.06 4.71 0.26 0.32 0.23 0.23 SEQID-03813 0.04 0.02 0.04 0.01 0.03 0.010.01 0.07 −21.63 0.35 0.00 6.96 0.26 0.31 0.32 0.30 SEQID-03814 0.020.07 0.02 0.10 0.05 0.06 0.03 0.05 −22.85 0.32 0.26 12.23 0.35 0.24 0.260.00 SEQID-03815 0.01 0.06 0.00 0.04 0.04 0.00 0.05 0.06 −26.78 0.290.16 11.14 0.26 0.28 0.25 0.27 SEQID-03816 0.02 0.12 0.02 0.08 0.08 0.030.05 0.02 −21.98 0.31 0.28 11.91 0.25 0.17 0.30 0.22 SEQID-03817 0.010.07 0.02 0.06 0.02 0.00 0.04 0.03 −28.81 0.21 0.17 11.50 0.27 0.28 0.250.23 SEQID-03818 0.02 0.04 0.02 0.03 0.04 0.02 0.05 0.05 −20.79 0.410.09 10.56 0.20 0.31 0.00 0.22 SEQID-03819 0.03 0.05 0.05 0.07 0.12 0.000.02 0.05 −25.03 0.29 −0.14 3.85 0.21 0.33 0.00 0.22 SEQID-03820 0.040.04 0.00 0.07 0.11 0.00 0.00 0.01 −25.34 0.08 −0.06 4.48 0.32 0.25 0.260.27 SEQID-03821 0.02 0.06 0.04 0.02 0.02 0.08 0.07 0.04 −25.02 0.160.01 7.95 0.21 0.33 0.00 0.23 SEQID-03822 0.03 0.05 0.05 0.14 0.05 0.030.02 0.03 −21.29 0.32 0.00 6.89 0.23 0.31 0.18 0.22 SEQID-03823 0.020.03 0.02 0.04 0.02 0.03 0.14 0.06 −30.29 0.05 0.06 9.65 0.24 0.26 0.000.21 SEQID-03824 0.05 0.04 0.07 0.02 0.01 0.00 0.02 0.04 −30.01 0.080.04 9.78 0.28 0.23 0.22 0.29 SEQID-03825 0.04 0.01 0.03 0.09 0.02 0.000.00 0.04 −31.12 0.21 −0.20 3.87 0.25 0.31 0.28 0.33 SEQID-03826 0.020.01 0.03 0.05 0.02 0.03 0.14 0.07 −22.84 0.23 −0.02 5.60 0.27 0.32 0.000.26 SEQID-03827 0.06 0.12 0.05 0.01 0.02 0.00 0.03 0.05 −26.24 0.22−0.24 3.42 0.32 0.23 0.30 0.28 SEQID-03828 0.03 0.04 0.03 0.02 0.04 0.020.05 0.04 −21.39 0.39 0.06 10.34 0.22 0.30 0.00 0.00 SEQID-03829 0.020.04 0.02 0.02 0.01 0.00 0.06 0.05 −31.10 0.27 0.26 10.97 0.31 0.26 0.280.26 SEQID-03830 0.08 0.02 0.04 0.05 0.00 0.00 0.00 0.01 −28.50 0.160.19 11.06 0.27 0.22 0.28 0.31 SEQID-03831 0.02 0.14 0.01 0.04 0.04 0.040.15 0.03 −20.48 0.33 0.10 9.76 0.24 0.20 0.26 0.26 SEQID-03832 0.040.02 0.03 0.02 0.08 0.00 0.04 0.12 −23.18 0.40 −0.07 4.32 0.26 0.34 0.250.26 SEQID-03833 0.05 0.01 0.00 0.05 0.09 0.04 0.06 0.07 −21.49 0.300.21 11.11 0.18 0.25 0.28 0.24 SEQID-03834 0.02 0.04 0.13 0.06 0.04 0.020.03 0.04 −20.06 0.25 0.04 9.69 0.23 0.35 0.21 0.25 SEQID-03835 0.040.05 0.03 0.04 0.05 0.06 0.03 0.00 −27.60 0.10 0.36 13.06 0.24 0.15 0.000.00 SEQID-03836 0.06 0.13 0.03 0.05 0.02 0.02 0.05 0.06 −20.29 0.42−0.01 6.51 0.24 0.29 0.23 0.00 SEQID-03837 0.02 0.11 0.01 0.12 0.05 0.030.03 0.06 −22.98 0.34 0.26 12.24 0.31 0.22 0.00 0.00 SEQID-03838 0.030.00 0.02 0.02 0.00 0.00 0.04 0.04 −28.59 0.44 0.33 12.09 0.34 0.18 0.320.27 SEQID-03839 0.03 0.02 0.14 0.05 0.02 0.00 0.02 0.04 −21.42 0.130.03 9.78 0.26 0.30 0.32 0.31 SEQID-03840 0.05 0.07 0.03 0.05 0.05 0.020.05 0.06 −19.97 0.34 −0.06 4.45 0.40 0.54 0.00 0.21 SEQID-03841 0.040.02 0.03 0.03 0.05 0.02 0.04 0.03 −21.54 0.49 0.12 11.67 0.21 0.31 0.000.21 SEQID-03842 0.02 0.04 0.00 0.09 0.03 0.00 0.05 0.05 −26.92 0.200.14 11.01 0.26 0.27 0.26 0.29 SEQID-03843 0.02 0.05 0.03 0.02 0.02 0.020.04 0.04 −21.07 0.42 0.06 10.30 0.20 0.31 0.00 0.00 SEQID-03844 0.030.02 0.05 0.14 0.04 0.01 0.04 0.05 −21.65 0.19 0.01 8.01 0.23 0.33 0.000.00 SEQID-03845 0.02 0.03 0.13 0.06 0.04 0.02 0.00 0.04 −24.03 0.220.05 10.20 0.26 0.30 0.27 0.27 SEQID-03846 0.01 0.12 0.04 0.07 0.04 0.010.05 0.04 −24.67 0.15 0.02 9.29 0.21 0.34 0.00 0.21 SEQID-03847 0.100.06 0.02 0.03 0.05 0.00 0.00 0.03 −27.07 0.07 0.33 13.12 0.25 0.20 0.000.00 SEQID-03848 0.09 0.06 0.02 0.07 0.02 0.00 0.16 0.02 −24.96 0.12−0.10 4.09 0.30 0.28 0.00 0.28 SEQID-03849 0.09 0.00 0.09 0.02 0.00 0.000.00 0.11 −23.49 0.40 0.25 11.37 0.33 0.16 0.33 0.33 SEQID-03850 0.030.07 0.04 0.07 0.08 0.02 0.03 0.08 −22.85 0.33 0.07 10.48 0.25 0.29 0.000.26 SEQID-03851 0.06 0.05 0.04 0.01 0.06 0.06 0.05 0.00 −27.66 0.080.32 12.62 0.29 0.18 0.00 0.29 SEQID-03852 0.03 0.03 0.07 0.02 0.06 0.000.02 0.02 −23.24 0.21 0.13 10.63 0.28 0.26 0.26 0.27 SEQID-03853 0.020.02 0.03 0.03 0.02 0.00 0.02 0.03 −38.14 0.22 −0.28 3.59 0.23 0.41 0.230.25 SEQID-03854 0.02 0.05 0.03 0.04 0.05 0.06 0.09 0.06 −20.82 0.21−0.01 6.58 0.23 0.35 0.00 0.22 SEQID-03855 0.02 0.00 0.00 0.04 0.01 0.000.05 0.04 −40.55 0.04 0.55 12.69 0.38 0.24 0.32 0.30 SEQID-03856 0.010.06 0.12 0.05 0.03 0.01 0.02 0.04 −21.58 0.29 0.01 7.37 0.21 0.31 0.210.00 SEQID-03857 0.01 0.04 0.03 0.03 0.07 0.00 0.07 0.14 −26.17 0.370.08 10.22 0.31 0.31 0.00 0.00 SEQID-03858 0.11 0.04 0.02 0.01 0.03 0.000.01 0.05 −23.03 0.26 −0.01 5.15 0.26 0.30 0.00 0.25 SEQID-03859 0.020.00 0.00 0.02 0.03 0.00 0.00 0.09 −37.46 0.02 0.04 9.75 0.31 0.21 0.280.32 SEQID-03860 0.01 0.01 0.05 0.00 0.01 0.05 0.15 0.05 −29.01 0.23−0.15 3.88 0.43 0.51 0.23 0.21 SEQID-03861 0.00 0.02 0.06 0.07 0.09 0.040.04 0.05 −30.00 0.10 0.34 12.54 0.24 0.23 0.00 0.23 SEQID-03862 0.030.12 0.03 0.05 0.05 0.01 0.02 0.05 −24.40 0.41 −0.06 4.40 0.24 0.35 0.210.24 SEQID-03863 0.05 0.02 0.02 0.15 0.04 0.00 0.02 0.06 −24.15 0.17−0.13 3.83 0.28 0.27 0.00 0.28 SEQID-03864 0.06 0.02 0.01 0.05 0.06 0.000.04 0.05 −24.03 0.22 0.14 11.24 0.30 0.31 0.00 0.24 SEQID-03865 0.050.02 0.00 0.05 0.04 0.00 0.00 0.07 −36.76 0.07 0.04 9.93 0.30 0.27 0.230.26 SEQID-03866 0.05 0.05 0.03 0.02 0.06 0.00 0.00 0.05 −21.90 0.14−0.14 3.67 0.28 0.27 0.31 0.00 SEQID-03867 0.01 0.04 0.02 0.00 0.12 0.000.07 0.13 −22.28 0.38 0.06 10.13 0.25 0.33 0.25 0.00 SEQID-03868 0.040.06 0.03 0.02 0.08 0.00 0.02 0.03 −25.74 0.09 0.31 12.57 0.30 0.24 0.000.25 SEQID-03869 0.03 0.07 0.04 0.06 0.07 0.02 0.05 0.06 −24.42 0.260.09 10.48 0.24 0.33 0.00 0.26 SEQID-03870 0.15 0.03 0.03 0.02 0.09 0.000.01 0.07 −21.44 0.24 −0.04 4.40 0.24 0.27 0.00 0.22 SEQID-03871 0.040.02 0.04 0.01 0.12 0.00 0.02 0.01 −27.74 0.20 0.14 10.57 0.32 0.23 0.300.33 SEQID-03872 0.02 0.05 0.03 0.08 0.06 0.04 0.07 0.06 −17.59 0.230.02 9.22 0.37 0.49 0.24 0.21 SEQID-03873 0.00 0.05 0.10 0.00 0.00 0.000.12 0.02 −23.97 0.19 −0.11 4.21 0.34 0.21 0.29 0.32 SEQID-03874 0.030.11 0.05 0.02 0.05 0.05 0.04 0.05 −26.20 0.42 0.15 10.69 0.31 0.13 0.290.31 SEQID-03875 0.02 0.06 0.02 0.07 0.04 0.00 0.00 0.02 −28.87 0.200.01 7.42 0.33 0.19 0.28 0.35 SEQID-03876 0.04 0.04 0.06 0.10 0.00 0.000.15 0.00 −21.57 0.23 0.27 11.87 0.35 0.11 0.27 0.35 SEQID-03877 0.030.04 0.05 0.10 0.11 0.01 0.04 0.07 −20.80 0.29 −0.08 4.25 0.00 0.33 0.160.18 SEQID-03878 0.06 0.00 0.03 0.08 0.10 0.00 0.02 0.04 −20.20 0.24−0.05 4.54 0.28 0.23 0.29 0.30 SEQID-03879 0.04 0.05 0.03 0.04 0.05 0.060.03 0.00 −27.60 0.10 0.36 13.00 0.26 0.17 0.27 0.00 SEQID-03880 0.030.03 0.04 0.07 0.08 0.00 0.00 0.04 −38.18 0.01 0.00 6.58 0.33 0.18 0.300.24 SEQID-03881 0.02 0.02 0.01 0.06 0.08 0.00 0.01 0.17 −24.25 0.36−0.05 4.62 0.26 0.31 0.26 0.25 SEQID-03882 0.04 0.02 0.07 0.15 0.02 0.000.05 0.04 −22.20 0.08 0.06 10.38 0.24 0.29 0.26 0.26 SEQID-03883 0.010.04 0.05 0.04 0.04 0.05 0.06 0.03 −31.29 0.25 −0.10 4.28 0.34 0.55 0.000.22 SEQID-03884 0.07 0.02 0.02 0.07 0.04 0.00 0.02 0.02 −23.97 0.240.03 9.28 0.27 0.26 0.00 0.27 SEQID-03885 0.01 0.04 0.07 0.05 0.03 0.010.03 0.03 −31.94 0.12 −0.09 4.39 0.23 0.34 0.21 0.24 SEQID-03886 0.060.08 0.05 0.02 0.00 0.02 0.05 0.06 −21.81 0.31 −0.02 6.00 0.23 0.32 0.220.00 SEQID-03887 0.06 0.06 0.05 0.03 0.00 0.02 0.05 0.05 −21.79 0.27−0.01 6.63 0.25 0.31 0.00 0.00 SEQID-03888 0.13 0.02 0.13 0.03 0.03 0.000.08 0.03 −22.77 0.03 0.18 11.37 0.29 0.18 0.25 0.30 SEQID-03889 0.020.02 0.01 0.07 0.05 0.01 0.01 0.04 −28.27 0.15 −0.06 4.67 0.00 0.36 0.160.19 SEQID-03890 0.03 0.00 0.01 0.00 0.04 0.05 0.14 0.00 −30.54 0.16−0.02 5.10 0.28 0.21 0.00 0.00 SEQID-03891 0.05 0.00 0.06 0.03 0.03 0.000.04 0.02 −31.55 0.14 0.05 9.84 0.28 0.18 0.29 0.28 SEQID-03892 0.030.00 0.02 0.03 0.05 0.06 0.10 0.02 −33.88 0.05 0.12 10.44 0.31 0.20 0.290.31 SEQID-03893 0.03 0.01 0.01 0.03 0.05 0.05 0.13 0.01 −34.98 0.090.09 10.08 0.31 0.21 0.27 0.32 SEQID-03894 0.03 0.01 0.01 0.02 0.04 0.050.12 0.01 −35.89 0.09 0.07 9.84 0.30 0.23 0.28 0.30 SEQID-03895 0.040.01 0.01 0.05 0.04 0.05 0.11 0.02 −34.48 0.10 0.05 9.55 0.30 0.25 0.280.29 SEQID-03896 0.02 0.00 0.03 0.06 0.05 0.00 0.10 0.08 −31.95 0.240.06 10.01 0.33 0.21 0.00 0.32 SEQID-03897 0.02 0.00 0.05 0.06 0.05 0.000.08 0.08 −33.43 0.21 0.08 10.22 0.27 0.17 0.00 0.34 SEQID-03898 0.010.02 0.04 0.05 0.05 0.00 0.08 0.07 −31.96 0.29 0.06 9.66 0.29 0.20 0.150.32 SEQID-03899 0.01 0.00 0.06 0.06 0.02 0.00 0.08 0.07 −31.03 0.210.08 10.25 0.27 0.19 0.27 0.27 SEQID-03900 0.00 0.00 0.02 0.03 0.00 0.100.08 0.06 −32.21 0.17 0.18 11.19 0.30 0.19 0.00 0.00 SEQID-03901 0.000.00 0.07 0.00 0.03 0.00 0.13 0.02 −31.13 0.24 −0.08 4.33 0.41 0.26 0.000.32 SEQID-03902 0.03 0.02 0.05 0.00 0.03 0.04 0.04 0.02 −30.04 0.230.20 11.63 0.29 0.19 0.33 0.23 SEQID-03903 0.02 0.02 0.02 0.00 0.03 0.020.13 0.02 −30.82 0.25 0.17 11.01 0.33 0.21 0.35 0.33 SEQID-03904 0.010.01 0.00 0.00 0.02 0.00 0.20 0.01 −31.14 0.38 −0.08 4.54 0.32 0.26 0.000.25 SEQID-03905 0.00 0.00 0.00 0.00 0.03 0.00 0.13 0.03 −30.46 0.340.00 6.81 0.34 0.22 0.00 0.00 SEQID-03906 0.00 0.03 0.02 0.03 0.00 0.040.11 0.02 −29.86 0.39 −0.02 5.79 0.29 0.19 0.20 0.31 SEQID-03907 0.010.02 0.06 0.00 0.02 0.06 0.23 0.01 −30.42 0.29 −0.16 3.92 0.32 0.22 0.230.32 SEQID-03908 0.03 0.02 0.02 0.06 0.02 0.00 0.10 0.03 −31.04 0.39−0.11 4.13 0.28 0.20 0.31 0.23 SEQID-03909 0.03 0.00 0.05 0.00 0.02 0.000.16 0.06 −31.07 0.42 −0.07 4.57 0.29 0.20 0.00 0.30

indicates data missing or illegible when filed

1.-44. (canceled)
 45. A nutritive formulation for the treatment orprevention of a muscle wasting disease, disorder or condition in a humansubject suffering from a renal disease, comprising an isolated nutritivepolypeptide comprising an amino acid sequence at least about 90%identical over at least about 50 amino acids to a polypeptide sequenceselected from the group consisting of SEQID 00001-03909; wherein thenutritive polypeptide is present in an amount sufficient to provide anutritional benefit to a human subject having or at risk of havingreduced protein absorption capacity; wherein the isolated nutritivepolypeptide has an aqueous solubility at pH 7 of at least 12.5 g/L andwherein the isolated nutritive polypeptide has a simulated gastricdigestion half-life of less than 30 minutes.
 46. The formulation ofclaim 45, wherein the polypeptide sequence comprises a ratio ofessential amino acid residues to total amino acid residues of at least34% and wherein the polypeptide sequence is nutritionally complete. 47.The formulation of claim 45, wherein the nutritive polypeptide isformulated in a pharmaceutically acceptable carrier, or wherein thenutritive polypeptide is formulated in or as a food or a foodingredient; or wherein the nutritive polypeptide is formulated in or asa beverage or a beverage ingredient.
 48. The formulation of claim 45,wherein the amino acid sequence encodes an enzyme having a primaryactivity, and wherein the nutritive polypeptide substantially lacks theprimary activity.
 49. The formulation of claim 45, further comprising acomponent selected from a tastant, a protein mixture, a polypeptide, apeptide, a free amino acid, a carbohydrate, a lipid, a mineral ormineral source, a vitamin, a supplement, an organism, a pharmaceutical,and an excipient.
 50. The formulation of claim 45, wherein theformulation is present as a liquid, semi-liquid or gel in a volume notgreater than about 500 ml or as a solid or semi-solid in a total massnot greater than about 200 g. 51.-64. (canceled)
 65. A method oftreating or reducing the severity of a renal disease in a human subject,comprising administering to the human subject a nutritional formulationin an amount sufficient to treat or prevent the renal disease, whereinthe nutritional formulation comprises an isolated nutritive polypeptidecomprising an amino acid sequence at least about 90% identical over atleast about 50 amino acids to a polypeptide sequence selected from thegroup consisting of SEQID 00001-03909.
 66. The method of claim 65,wherein the isolated nutritive polypeptide has an aqueous solubility atpH 7 of at least 12.5, 20, 30, 50, or 100 g/L.
 67. The method of claim65, wherein the isolated nutritive polypeptide has a simulated gastricdigestion half-life of less than 2, 10, 30, or 60 minutes.
 68. Themethod of claim 65, wherein the isolated nutritive polypeptide does notform insoluble aggregates at 95° C., pH 7.1, when present at 10 mg/ml.69. The method of claim 65, wherein the formulation further comprises apharmaceutically acceptable carrier.
 70. The method of claim 65, whereinthe formulation is present as a liquid, semi-liquid or gel in a volumenot greater than about 500 ml or as a solid or semi-solid in a totalmass not greater than about 200 g; and wherein the formulation issubstantially free of non-comestible products.
 71. The method of claim65, wherein the formulation further comprises a component selected froma tastant, a protein mixture, a polypeptide, a peptide, a free aminoacid, a carbohydrate, a lipid, a mineral or mineral source, a vitamin, asupplement, an organism, a pharmaceutical, and an excipient.
 72. Themethod of claim 65, wherein the human subject is at risk of developingmalnutrition or protein malnutrition.
 73. The method of claim 65,wherein the human subject has chronic renal failure, acute renalfailure, glomerulonephritis, glomerulonephrosis, tubular nephritis,interstitial nephritis, or nephrotic syndrome.
 74. The method of claim65, wherein the human subject has end-stage renal disease or a nephroticsyndrome.
 75. The method of claim 65, wherein the human subject has aurea cycle disorder.
 76. The method of claim 65, wherein the humansubject suffers from a muscle wasting condition.
 77. The method of claim65, wherein the nutritional formulation is administered as an adjunct toadministration of a pharmaceutical composition.
 78. The method of claim65, wherein the human subject is suffering from a renal disease and hasreceived one or more doses of a pharmaceutical composition, wherein i)the disease, disorder or condition or ii) the administration of thepharmaceutical composition, or both i) and ii) increases a risk of lossof muscle mass and/or muscle function.